News this Week

Science  21 Sep 2012:
Vol. 337, Issue 6101, pp. 1438
  1. Around the World

    1 - Beijing
    Censured Chinese Official's Promotion Ignites Anger
    2 - Washington, D.C.
    A Forbidding Budget Outlook
    3 - Tokyo
    Japan to Phase Out Nuclear Power, End Monju Project
    4 - Laos
    Child Mortality Falls, but Not Fast Enough


    Censured Chinese Official's Promotion Ignites Anger


    An official who was reprimanded after a 2008 scandal involving tainted baby formula has been promoted to deputy director of China's State Food and Drug Administration, sparking calls for transparency. Sun Xianze formerly oversaw food safety for the agency. He was issued an official demerit in 2009, after six infants died and nearly 300,000 fell sick from ingesting milk powder laced with melamine, an industrial chemical that causes kidney damage. Sun was one of dozens of officials censured in the wake of the tragedy, which also brought a government pledge to improve food safety (Science, 28 November 2008, p. 1310).

    Under the terms of Sun's demerit, he was not allowed to advance in the agency for 12 months—a term he has since served. Still, his promotion brought public outrage. Li Fangping, a lawyer who defended victims in the scandal, called for greater openness. “There should be public release of his résumé and wrongdoings before the promotion,” he told China's Global Times.

    Washington, D.C.

    A Forbidding Budget Outlook

    A spending freeze for now—but deep cuts may come later. That's the message sent to U.S. government science programs by two recent federal budget developments. This week, Congress was expected to finalize a temporary spending bill that will fund government operations through 27 March 2013. The deal avoids a government shutdown and gives lawmakers more time to resolve spending disagreements over the 2013 fiscal year, which begins on 1 October. This stop-gap measure freezes most agency budgets at current levels (providing a tiny 0.612% increase), but gives the National Oceanic and Atmospheric Administration some extra cash to prevent further delays in two Earth-observing programs, the Geostationary Operational Environmental Satellite-R initiative and the Joint Polar Satellite System. But those and other science programs face major spending cuts if by the end of the year Congress can't reach a long-term deal to reduce U.S. deficits, the White House warned on 14 September. Spending on civilian research would shrink by 8.2%, and defense research by 9.4%, under an existing law that would impose across-the-board cuts on 2 January 2013 unless lawmakers act. Science advocates are imploring lawmakers to prevent the automatic “sequester,” arguing it would devastate research.


    Japan to Phase Out Nuclear Power, End Monju Project


    Japan is embarking on a plan to end the use of nuclear power by sometime in the 2030s and convert the Monju experimental fast breeder reactor into a nuclear waste transmutation facility with a limited but unspecified lifetime. The policy rethink was triggered by the March 2011 disaster at the Fukushima Daiichi Nuclear Power Plant and reverses a 2010 plan that called for boosting reliance on nuclear power from about 30% to 45% of generating capacity by mid-century. Existing reactors will be shut down after 40 years of operation. The new energy policy, endorsed by a Cabinet panel last week, shifts the focus to conservation and renewable energy sources.

    What will happen to nuclear power-related research “is yet to be discussed,” says Satoru Tanaka, a University of Tokyo nuclear engineer and former president of the Atomic Energy Society of Japan. It is also possible that the political party that wins the national elections, likely to be held before the end of this year, could revisit the decision to phase out nuclear power.


    Child Mortality Falls, but Not Fast Enough


    The Lao People's Democratic Republic cut its child mortality rate by 72% between 1990 and 2011. That's one of the most dramatic reductions detailed in a report released on 13 September by UNICEF, the World Health Organization, the World Bank, and the U.N. Population Division. Global child mortality has fallen by 41% since 1990, according to the new statistics—good news, but still not good enough to meet the Millennium Development Goal 4, which aims for a two-thirds reduction in child mortality between 1990 and 2015.

    Sub-Saharan Africa and Southern Asia accounted for more than 80% of global deaths among children younger than 5 in 2011. Nearly a quarter of child deaths were in India, in part because of its large population. The leading cause of death was pneumonia, responsible for 18% of worldwide deaths in children younger than 5, followed by preterm birth complications, which accounted for 14%.

    Besides scaling up basic health services, educating girls and women has significant impact on child survival, the report says.

  2. Random Sample

    Pet Monkey Turns Out to Be New Species


    Conservation biologist John Hart didn't set out to bag a monkey unknown to science. He wanted to survey bonobos in the unexplored lowland rainforest of the Democratic Republic of the Congo's Lomani basin. But a colleague's photograph of an unusual monkey on a bushmeat hunter's canoe changed his mind. Learning that a schoolmaster's daughter living on the edge of the forest had adopted one of the young monkeys as a pet, Hart—with the Lukuru Wildlife Research Foundation in Kinshasa—and colleagues tracked its growth for the next 19 months. They also observed the primate in the wild. Unlike many of its cousins, the monkey, locally known as lesula, spends most of the time foraging quietly on the ground in small groups. Shortly before dawn, they liven up the forest with “boom” calls, but are otherwise hard to detect. On 12 September in PLoS ONE, Hart and his colleagues described Cercopithecus lomamiensis—the second African monkey to be “discovered” in 28 years. They are now monitoring the wild monkeys with camera traps and are working toward making the area a national park.

    Citizen Science on the Sea Floor

    Calling all fish finders and scallop spotters: Seafloor Explorer needs your help! Launched on 13 September, this interactive Web site asks ordinary people to help spot interesting critters and objects in photographs of the ocean floor. Researchers hope these citizen scientists can help them analyze the deluge of images (some 3 million per day) captured by an underwater vehicle called the HABitat mapping CAMera System (HabCam). Towed over the sea floor along the U.S. East Coast, HabCam has produced more than 500 million pictures that need analysis. For now, just 100,000 of them have been uploaded to the Seafloor Explorer site, but scientists plan to add more soon. “The information that we're gathering, at least initially, is to help support our ability to collect information on the interaction between different organisms, like sea stars and their predators,” says biologist Scott Gallager of the Woods Hole Oceanographic Institution in Massachusetts. Gallager also hopes that once enough pictures are analyzed, he can use the database to develop an automated classification system for HabCam's images. Seafloor Explorer is the latest crowdsourcing project from Citizen Science Alliance (CSA), the team behind Galaxy Zoo and other citizen science initiatives available on “The techniques have been refined over a number of projects now, and seem to produce excellent science,” says Arfon Smith, CSA director. Zooniverse projects have resulted in at least 40 peer-reviewed papers, and Smith is confident that the data from Seafloor Explorer will bump that number even higher. Check out Seafloor Explorer at


    By the Numbers

    56.7°C — Hottest official temperature on Earth, recorded in Death Valley in 1913. In a 13 September announcement, the World Meteorological Organization (WMO) stripped Libya of its 90-year claim to the title after a WMO investigation concluded that the country's chart-topping 58°C temperature had been recorded incorrectly.

    1.2 million square kilometers — Projected increase in global urban land area by 2030. This would triple the global coverage recorded in 2000, according to a study published online on 17 September in the Proceedings of the National Academy of Sciences.


    Join us on Thursday, 27 September, at 3 p.m. EDT for a live chat on the scientific job market.

  3. Newsmakers

    NIH Picks Translational Center Chief



    The National Institutes of Health has chosen developmental neurogeneticist Christopher Austin to direct its 9-month-old National Center for Advancing Translational Sciences (NCATS). He starts on 23 September and will head a $575 million agency aimed at addressing bottlenecks in the drug development process.

    Austin, who turns 52 next week, has spent most of the past decade at the National Human Genome Research Institute, where he launched a set of small-molecule screening centers and headed programs such as drug development for rare and neglected diseases. Before that, he worked on genome-based drug discovery at Merck for 7 years.

    Austin described his promotion as the “culmination” of career-long efforts to bridge basic research and the clinic. “This is a really hard, ambitious, but deeply important mission we're all on,” he told NCATS's advisory council last week.

    Steven Paul, a former Eli Lilly research chief now at Weill Cornell Medical College in New York City who served on the search committee, says: “We came up with a terrific person. … Chris has credibility with both academic investigators and the private sector.”

    Three Q's

    Mote Jr.


    The National Academy of Engineering (NAE) has nominated mechanical engineer C. Daniel Mote Jr., former president of the University of Maryland, College Park, from 1998 to 2010, as its next president. If elected by the academy's membership, Mote will succeed current president Charles Vest when Vest's term ends on 30 June 2013.

    Q:What challenges does the academic engineering community—and the U.S. engineering enterprise—face today?

    Many of the challenges they face are related to funding, but also the national commitment to basic research and the competitiveness of U.S. research globally. Since 1990, the world has been moving into a globalization mode. It is no longer about controlling information and products. Now, the game is to engage globally to develop your products.

    Q:What will your priorities be as president of the academy?

    We need to capitalize on NAE programs that create a flexible and agile engineering talent base. We also need to update continuing education efforts. This responsibility has to fall on universities and colleges in the coming years. They have traditionally seen this as an auxiliary responsibility but that needs to change.

    Q:Will international collaborations help or hurt efforts to foster innovation in the United States?

    There is a tendency in this country to think that collaboration means the U.S. gives away knowledge. With collaborations, everybody gets something. It's hard to sell products to different countries if you don't understand what they want and why. If people spend time in different countries, you understand this picture a lot better.


    Amy Bishop, a former assistant professor of biology at the University of Alabama, Huntsville, who shot and killed three fellow faculty members and injured three more in 2010 after being denied tenure, pleaded guilty last week to capital murder charges. Under the terms of the plea, she'll avoid the possibility of the death penalty and will instead be sentenced to life in prison.

  4. Biometrics

    China's Sharp Focus on Biometrics

    1. Mara Hvistendahl

    The country is making advances in biometrics research applications such as intelligent surveillance and infrared face recognition—and raising concerns among privacy advocates.


    SHANGHAI, CHINA—Security cameras are ubiquitous in Chinese cities: peering along corridors, surveying busy streets, scanning public spaces. Over the past decade, the country has steadily ramped up surveillance efforts, setting a target of installing 30 million security cameras by 2015, or roughly one for every 45 people.

    The sheer number of cameras dotting urban China, coupled with the limited power of civic groups to safeguard the rights of those being watched, gives privacy advocates pause. But the proliferation also poses problems for the watchers: Footage is typically reviewed manually, by police officers sitting in front of a screen searching for a specific crime, says Stan Z. Li, director of the Center for Biometrics and Security Research at the Chinese Academy of Sciences' Institute of Automation (CASIA) in Beijing. Hunting down a suspect's mug can take weeks or even months, he says: “It's very tedious. There is a huge, urgent demand for intelligent video analysis.”

    That's where Li and his colleagues come in. Li, who advises the central government on building an intelligent video surveillance infrastructure, has developed an application called VSearch that “makes the impossible possible,” he says. Through pattern recognition and data mining, it allows users to scan footage for people that fit certain descriptions. With closed-circuit television (CCTV) footage of a suspect wearing a red T-shirt and jeans, for example, officers can search other footage for individuals who fit the bill. VSearch works similarly for cars, searching by color and shape. “We can help the user find what he needs from a huge amount of data,” Li says. “We've reduced the workload significantly.”

    Biometrics—a field that grew out of fingerprinting to encompass emerging areas like gait and heartbeat recognition—is in its heyday in China. A large research force, generous government support, and advances in the algorithm speeds that enable biometric applications have pushed innovation in areas like intelligent surveillance and infrared face recognition. The leading Chinese image-processing and machine-learning labs now “compete with the top institutions in the U.S.,” says Anil K. Jain, a computer scientist at Michigan State University in East Lansing who sits on the advisory board of CASIA's Center for Biometrics and Security Research and makes yearly visits to Beijing to meet with Chinese counterparts. The number of publications from China is “quite impressive,” says Sébastien Marcel, an expert on pattern recognition and machine learning at Idiap Research Institute in Martigny, Switzerland.

    Chinese biometric applications are being put to use for security in areas such as banking and sporting events—as they are in countries like the United Kingdom, where surveillance cameras are also ubiquitous. But critics worry that concerns about an Orwellian state—often overblown in the past—are finally well-founded. They fear that the new technologies will help China's one-party state clamp down on dissent and monitor political opponents. Technologies that allow authorities to quickly sift through vast amounts of data “really raise the specter of a Big Brother society,” says Nicholas Bequelin, a researcher at Human Rights Watch in Hong Kong. In China, he adds, “there will be a sea change in the ability of the security agencies to monitor nationwide specific individuals—for law-enforcement purposes, but also for political motives.”

    An unlikely catalyst

    China's involvement with biometrics dates to the 1980s, when the Ministry of Public Security funded research at Tsinghua University and Peking University on fingerprint authentication, says Zhou Jie, a computer scientist at Tsinghua University in Beijing. Globally, work on biometric recognition was coming into its own. In 1987, Lawrence Sirovich and Michael Kirby, mathematicians at Brown University, discovered a way to analyze faces, essentially by turning images into vectors made up of pixels. Those processed images, called eigenfaces, paved the way for accurate face-recognition technology.

    Sophisticated security equipment soon proved its worth to Chinese authorities. Footage from surveillance cameras helped security forces identify students and workers who had been in and around Tiananmen Square during the 1989 protests. The cameras had been manufactured by a U.K. company and their installation paid for by the World Bank, according to a report by the now-defunct Canadian government agency Rights & Democracy. In the wake of the crackdown, the U.S. Congress enacted export restrictions banning the transfer of crime-fighting equipment—including biometric technologies like fingerprint scanners—to China.

    Those export controls sparked China's biometrics boom. Chinese researchers “had to start from scratch,” Jain says, by building homegrown versions of Western technologies. China began rolling out its technologies on a large scale in 2004, when checkpoints on the Hong Kong–mainland border installed face- and fingerprint-recognition systems for Hong Kong residents who frequently cross the border.

    A series of ambitious projects followed. At the 2008 Beijing Olympics, face-recognition systems provided by the Beijing company AuthenMetric helped verify attendees at the opening and closing ceremonies, by comparing their faces to photos on their ticket application forms. The stadium hosting softball games used hand-vein recognition to control access to the stands. Today, research into China's third-generation identification cards, which will use fingerprinting, are giving the industry another boost, Zhou says.

    Changing faces.

    A face looks different in the visual spectrum when lighting conditions change (top row), but infrared images stay the same (bottom row).


    Li sums up the advantages of working in China in one word: “People.” “It's not unusual for a professor to have 20 graduate students working on face recognition,” Jain says. That workforce came in handy in a venture overseen by Song-Chun Zhu, a computer scientist at the University of California, Los Angeles. Zhu developed a technology that converts images into text—another way to achieve Li's goal of making video searchable. Much of the grunt work was done at the Lotus Hill Institute for Computer Vision and Information Science, which Zhu established in his hometown of Ezhou, Hubei Province, in 2005. He hired graduates of local art colleges to annotate images, affixing them with labels from a predetermined group of categories. The employees focused on people and cars, and just those two tasks kept them busy for years. But by 2010, the lab had built a database of 2 million images containing objects in 500 categories.

    Although Zhou says China still lags behind other countries in the development and application of biometric technologies, it is now tackling problems that vex researchers around the world. Take spoofing. Standard face-recognition systems can be fooled by a person holding up a photo of another individual's face. In response to that and other challenges, Li developed infrared face recognition. The application, which was used to confirm the identity of workers at Expo 2010 Shanghai China, “has a natural immunity to photos, because it uses different imaging-process principles,” Li says. Two spectra—one visual and one infrared—make it robust, adds Marcel, who coordinates Trusted Biometrics under Spoofing Attacks, an E.U. project to combat fraud in biometric technologies. CASIA is a collaborator on the project.

    Chinese researchers are also tackling a more intractable problem: “noncooperative” face recognition. While technologies like Li's allow police to search for clothing and other identifiers, pinpointing specific faces in surveillance footage is still impossible. Existing recognition technologies work best in controlled, evenly lit environments like security checkpoints, where subjects are facing one direction and positioned a certain distance from the camera. That could change if researchers can develop technologies for recognizing faces from different angles, in variable lighting, and over time, as a person's appearance changes. “The most significant challenge is aging,” Li says. “That's an unsolved problem.”

    The specter of interoperability

    In a presentation at the 2009 Asian Biometrics Consortium conference in Tokyo, Tan Tieniu, director of CASIA's National Laboratory of Pattern Recognition, said that among the sites targeted for iris-recognition systems and other biometric technologies in coming years are the country's thousands of prisons, detention houses, and labor camps—sites that house dissidents as well as prisoners. And the new flood of research follows on the development of an extensive surveillance system. In 1988, only 2% of local budgets went toward public security, according to Christian Göbel, a political scientist at Heidelberg University in Germany and Lund University in Sweden. By 2010, that figure had increased to 6%, Göbel says—and the rise in absolute terms was even starker.

    Today, lampposts in Tiananmen Square are studded with cameras, as are the homes of political dissidents. After a series of protests in Tibet in 2008, the Chinese government installed cameras at monasteries throughout the autonomous area. Riots the following year in Xinjiang, a heavily Muslim region plagued by unrest, brought a similar response, Bequelin says: “There was a very clear policy of installing cameras to identify people and to monitor in a way that was intimidating.”

    The lack of citizen protections in China allows for greater latitude in employing biometric technologies. In China “you are able to cross images gathered from a CCTV system with other databases,” Bequelin says: “The key here is interoperability.” The Shenzhen company China Information Security Technology Inc. is developing an identification card for migrant workers that its Web site says will be traceable through police geographical information systems. “The [privacy] issue doesn't exist in China,” Jain says.

    To be sure, many of the technologies being developed in China do not have sinister uses. Fingerprinting is used in some provinces to verify the identities of students taking China's annual university entrance examination. Coal mines in northeastern China use an iris-recognition system that grew out of research done at CASIA to control access and keep track of workers during an accident. “These technologies help to sustain authoritarian rule in China, but they're not only there for that,” Göbel says. “They also address concerns of the population.” And yet, Bequelin says, such dual-use technologies should be monitored “by a strong civil society or a political system that is responsive to citizens' concerns.” In China, he adds, that “is just not there.”

  5. Infectious Disease

    Despite Setbacks, Optimism on Drugs for Hepatitis C

    1. Jon Cohen

    Researchers have hit speed bumps on the road they hope will soon lead to a safe, short course of treatment that will rid the body of this liver-damaging virus.

    When a promising drug fails in clinical trials, it's usually no more surprising than a star baseball player striking out: Failure is the name of the game. But when Bristol-Myers Squibb (BMS) announced on 23 August that it was pulling the plug on a drug against hepatitis C virus (HCV) because of toxicity, disappointment reverberated throughout the field. Hopes were high for the drug: It was one of the furthest along in clinical trials of a new class of agents against HCV, and the Princeton, New Jersey, pharmaceutical giant had deemed it so likely to become a backbone of treatment that it paid $2.5 billion in February to acquire the small company then developing the compound.

    First in class.

    Norbert Bischofberger of Gilead says its “nuke” inhibitor has a clean record so far.


    Researchers are now trying to understand why the drug failed and the impact it might have on other drugs in the pipeline—some of which work through similar mechanisms. Most are cautiously optimistic, however, that other drugs in development will pan out and that the failure will not seriously dent hopes of curing the disease with a short, relatively safe course of treatment that would work worldwide.

    The hepatitis C field was buoyed last year when the first two drugs that directly attack the virus came to market. “It's a very exciting time,” says virologist Mark Sulkowski, medical director of the Viral Hepatitis Center at the Johns Hopkins University School of Medicine in Baltimore, Maryland. “We can begin to envision the possibility of making a big difference both on an individual patient level and, even more expansively, on a population level.” In keeping with that therapeutic optimism, the U.S. Centers for Disease Control and Prevention last month announced a major push to identify HCV-infected baby boomers in the United States—the most affected age group—and bring them into care (Science, 24 August, p. 903).

    Hepatitis C treatment represents a huge potential marketplace, and better drugs are badly needed. The World Health Organization estimates that HCV chronically infects 150 million people in the world. Although 15% to 25% of those infected will clear the virus without treatment, up to 20% of the chronically infected develop cirrhosis, and 1% to 5% will die from liver cancer or liver failure. The mainstay of treatment until 2011 was two drugs that have both antiviral and immune-stimulating properties. One is α-interferon, a natural protein protected with polyethylene glycol (“pegylated”) so it is released slowly into the bloodstream; it must be injected and has high toxicity. The second is a pill, ribavirin, that interferes with RNA metabolism. There are at least six different genotypes of HCV, and the drugs work better against some than others; genotype 1, which accounts for 60% of the infections in the world, is the hardest to treat. Genetics also has a major impact on a person's response to treatment. What's more, neither of these drugs directly attacks the virus, their mechanisms of action remain murky, they cost up to $20,000 for a treatment course that runs from 24 to 48 weeks, and more than half the people who take them are not cured. (A cure is defined as a “sustained virological response-24,” or SVR-24, in which the virus can't be detected for more than 24 weeks after treatment stops.)

    The two direct-acting antiviral drugs that came to market last year both specifically cripple an HCV enzyme, protease. They must be taken with interferon and ribavirin, and although these combinations have higher cure rates—they work in roughly three of four people—they have extra toxicities and can cost up to $50,000 per course. They are approved only for genotype 1, which is responsible for 75% of the estimated 3.2 million chronic infections in the United States, the country with the most attractive marketplace.

    The BMS drug that failed in clinical trials inhibits a different enzyme, polymerase, that the virus needs to copy itself. Like several other compounds in development that target HCV polymerase, it works against all genotypes and has a high barrier to the development of drug-resistance mutations. “These drugs are difficult for the virus to evade, and that's led them to be very attractive,” Sulkowski says. Researchers were hopeful that the BMS drug could be combined with other direct-acting antiviral drugs to provide a cure without the need for interferon injections. But the company scuttled the drug after serious liver and heart toxicities surfaced in a phase II clinical trial, sending nine patients to the hospital, one of whom died. The U.S. Food and Drug Administration put a “clinical hold” on a similar compound made by Idenix Pharmaceuticals also in phase II trials—and there may be a ripple effect on other drugs in development. “I think it will have an impact on how regulatory agencies evaluate the safety of all of these drugs,” says David Nelson, a hepatologist at the University of Florida, Gainesville. “There's a mad rush to move forward with these all-oral drugs, rightly so, but it will lead to a rethinking.”

    Drugs in development have four different viral targets, and many researchers believe that hitting HCV from different angles is the best way to defeat it (see table). The polymerase inhibitors like the BMS candidate put nucleotide or nucleoside analogs into the viral RNA to cripple it, and they are known as “nukes.” Clinical trials are also under way on “non-nuke” polymerase inhibitors that work by other mechanisms. New protease inhibitors are in phase II and III clinical trials, as are inhibitors of HCV's NS5A replication complex protein.

    But the removal of the BMS drug and, potentially, the one made by Idenix narrows the pipeline for the nuke class. Several other promising compounds in every class have also failed in the past year. “A year ago, when all of these things were still looking good, there was a lot of talk about an interferon-free, direct-acting antiviral combo succeeding, and the game is over,” says virologist Charles Rice of The Rockefeller University in New York City. “It's amazing to me what the failure rate still is.”

    One nuke polymerase inhibitor has moved all the way to the final phase of clinical testing, phase III, and has a clean toxicity record. Known as GS-7977, the compound was first made by Pharmasset in Princeton, New Jersey, which Gilead Sciences in Foster City, California, acquired in January for $11.2 billion largely because of the drug's “outstanding” early performance in human studies, says Norbert Bischofberger, Gilead's chief scientific officer. “We felt very comfortable about the compound,” he says. (Another nuke included in the deal went by the wayside because it, too, had serious toxicities.)


    Bischofberger suggests that there's less concern about toxicity with GS-7977 than the BMS and Idenix nukes for several reasons. One is that GS-7977 differs in both structure and the mechanism of action from the BMS and Idenix nukes. Secondly, the Gilead drug has also been given to many more patients than the BMS one—about 2000 compared to 250. No one knows why the toxicities surfaced with the BMS drug, but Bischofberger suspects the drug might interfere with the working of mitochondria, which has occurred with some anti-HIV nukes. Mitochondria are energy factories, and both the heart and kidney are highly energy-dependent organs.

    In small studies, GS-7977 combined with either ribavirin or an NS5A inhibitor made by BMS has had 100% cure rates. “Everyone hopes 7977 or one of these other nukes will be the cornerstone of an interferon-free regimen,” says Rockefeller's Rice. Studies that combine GS-7977 with the less appealing α-interferon and ribavirin are furthest along, however, and Bischofberger says the company might seek regulatory approval for that cocktail as early as mid-2013. The cocktail is being tested against all six genotypes.

    Although much excitement exists about the prospects of the new era of HCV treatment, researchers stress that the many drug combinations now being tested still might not work in some people. All the drugs in development, including GS-7977, have not been as effective in people who failed earlier on α-interferon and ribavirin. It is not immediately clear why this would be so: Those older drugs don't directly act against the virus, so using them theoretically shouldn't create drug-resistant mutations that compromise direct-acting antiviral drugs. The UniUniversity of Florida's Nelson says the failure may simply flag the fact that some people have a genetic background that undermines treatment efforts.

    Sulkowski of Johns Hopkins and colleagues revealed in the 17 September 2009 issue of Nature that genetic variations near a gene known as IL28B determined who best responded to the α-interferon/ribavirin regimen. Specifically, the IL28B CC genotype found in European populations had about a twofold higher success rate with treatment than the IL28B TT genotype commonly found in African-American and Hispanic populations (Science, 29 October 2010, p. 579). Nelson says the IL28B TT genotype might be a marker that people have compromised innate immune responses. “You need innate immunity to control removing hepatitis C from the cells,” Nelson says. “Non-responders who have the IL28B TT allele have a different innate immunity in the liver that probably raises the barrier to what drugs you'll need.”

    Gilead's Bischofberger suspects that the problem might not be so intractable. He says α-interferon and ribavirin may create non-responders by, say, leading HCV out of the liver and into another part of the body that the direct-acting drugs have more trouble reaching. He says studies under way that treat naïve populations with only direct-acting antiviral drugs will reveal whether nonresponders are a genetic phenomenon or a consequence of α-interferon/ribavirin treatment.

    Current treatments work best in people during early stages of disease, and Rockefeller's Rice worries that the new drugs similarly may work well in people with mild liver disease but not in those with cirrhosis. “People in the greatest need of being treated and cured have the poorest response rates, and they aren't the front runners for early-stage clinical trials so there's not as much data for how these drugs are going to work in these populations,” Rice says.

    Still, in spite of the failure of the BMS drug, the future looks so bright for HCV treatment that many clinicians are encouraging infected patients to wait to start treatment until the next crop of drugs comes to market that are more effective, safer, and require shorter times to bring about a cure. “Clearly, patients with milder liver disease have reason to wait,” says Nelson, who expects several powerful new regimens on the market within 3 to 5 years. Rice is more cautious. “We shouldn't say the game is over until it's over,” he says, borrowing a line from baseball legend Yogi Berra. “We need a good stable of these compounds, and it's probably going to take a while to get there.”

  6. Task Force's Prevention Advice Proves Hard to Swallow

    1. Eliot Marshall

    In an interview with Science, the current chair of the U.S. Preventive Services Task Force defends the panel's controversial decisions on issues such as cancer screening.

    Virginia Moyer, a pediatrician with a keen interest in health screening, remembers what it was like to be on the U.S. Preventive Services Task Force (USPSTF) before it became notorious—back when “we felt like we were toiling in obscurity.” Created by the Department of Health and Human Services (HHS) 3 decades ago, the panel examines clinical data and decides whether methods of preventing disease—many of them already in use—are backed by evidence that they're worth using. Moyer's USPSTF term began in 2003 and except for a 2-year break, she has served ever since, becoming its chair in 2011. It was in 2009 that she and the rest of the task force shed their relative anonymity when they addressed a question many had thought settled: Should healthy women in their 40s get an annual mammogram?

    The panel's explosive answer: No, because giving such advice would do more harm than good. It would lead to a huge number of false alarms and biopsies, the 16-member task force found, but would do little to reduce cancer deaths.

    That's not how the panel worded its conclusion, however. Using carefully honed metrics, it gave a “C” grade (meaning weak) to evidence for benefits of mammography in this age group, a topic the task force had studied in various ways for years. After failing to agree on a first vote, USPSTF had commissioned new modeling studies to clarify risks and benefits. Then the majority voted “against” a proposed recommendation that 40-year-olds get annual mammograms.


    Pediatrician Virginia Moyer likes to ask, “Why are we doing this?”


    Turmoil ensued. Congressional committees grilled USPSTF members—nearly all of whom were physicians or nurses, and many of whom had Ph.D.s. Critics hastened to point out that none were cancer specialists. Advocates of mammography complained that a nerdy committee was trying to cut medical benefits. Radiologists claimed that, maybe because panel members didn't work directly with cancer patients, they under valued the lifesaving power of mammography. Kathleen Sebelius, the HHS secretary, went on television to urge calm, arguably undercutting the panel by asking women to “do what you've always done: … Talk to your doctor” (Science, 19 February 2010, p. 936).

    The noisy response was partly the result of bad timing, says Moyer, a professor at Baylor College of Medicine in Houston, Texas. The task force issued its finding in the fall of 2009 when debate over the Administration's health care reform was raging and congressional election campaigns were heating up. It was a “perfect storm,” agrees epidemiologist J. Michael McGinnis, an advocate of preventive health care and senior scholar at the Institute of Medicine in Washington, D.C.

    USPSTF touched off another furor in May 2012 when it voted to reject a widely used method of screening for prostate cancer: the blood test based on prostate-specific antigen (PSA). In this case, USPSTF found strong negative evidence and concluded that routine screening of healthy men should stop. Urologists were outraged; since then, their professional associations have urged Congress to overhaul USPSTF. They want medical specialists like themselves seated on future USPSTF panels.

    McGinnis says he expected some storms both within and outside government when, as a top HHS official, he created USPSTF in 1984. That's why HHS set it up as an independent body: “We wanted them to be totally unfettered by anything but the evidence in the way they went about their business.” But the nature of controversy has changed since the 1980s. When USPSTF began, McGinnis says, he imagined that it would highlight the benefits of preventive services, “to show that the evidence base for prevention was even stronger than for many treatment interventions.” At the time, clinical medicine “was overwhelmingly focused on the treatment side,” McGinnis says.

    McGinnis, who started in the Carter Administration and also served under presidents Ronald Reagan and Bill Clinton, agrees with Moyer that the 2009 storm over mammography was partly about politics. But he says that experts were at odds, and that unlucky timing and “poor communication” of findings contributed to USPSTF's woes.

    Ned Calonge, the physician-epidemiologist who was chair of USPSTF when it made its mammography recommendations in 2009, says that what really surprised him was being shut out of the subsequent public debate. “It was frustrating to me not being able to counteract the very carefully crafted misinformation from the advocates” of mammography screening, says Calonge, now CEO of The Colorado Trust in Denver, a philanthropy. “We could not get control of the message.”

    In its early days, USPSTF undertook two reviews of more than 150 preventive measures—trying to cover the universe, McGinnis says. But medicine was changing too rapidly to keep up this pace; in the late 1990s the panel switched to doing analyses of single topics, which it now selects with input from researchers and the public. This year, for example, more than 20 topics are under review, from screening for abdominal aortic aneurysms to the use of vitamin D supplements to prevent cancer and osteoporosis.

    Calonge, Moyer, and McGinnis all say that USPSTF needs to learn to communicate findings more clearly. And they agree on another point: A bill proposed in Congress this year to revamp USPSTF would not be a great way to improve scientific reviews. Introduced by Representative Marsha Blackburn (R–TN) and others, the USPSTF Transparency and Accountability Act of 2012 (H.R. 5998) would require the task force to include “stakeholders” and “specialty care providers” on decision-making panels. This is the plan backed by urological associations.

    Moyer acknowledges that the task force can use advice from medical specialists, but only if they are experienced in clinical epidemiology and primary care—and are thoroughly impartial. Recruiting advocates as reviewers would defeat the purpose of the task force, she says.

    Time is running out for the Blackburn bill in this Congress. But if it fails this year, the appeal to shake up USPSTF by including advocates may come back in 2013. Science recently spoke with Moyer about her role, her task force's recent fame, and its future. Her answers have been edited for brevity and clarity.

    Q:How did you get into this field?

    V.M.:I think I got into evidence-based medicine because I tend to say, why are we doing this? (I have a journalist father and a scientist mother.) I was extremely fortunate to go to an early workshop sponsored by McMaster University, one of the birthplaces of evidence-based medicine. I got very involved. … I had written a paper about whether there was any evidence for what we do in pediatric checkups. I looked at procedures that were recommended by at least two august bodies for these checkups and dug up the evidence for them, and it turns out there's not a lot of it. That doesn't mean they don't work.

    Q:On the task force, was there concern about potential harms from preventive measures from the beginning?

    V.M.:Yes, this was a new way of looking at things. We don't just say, “Oh, prevention is wonderful.” As in all of medicine, you have to look at the upsides and the downsides, the benefits and the harms. … If you have someone who feels fine when they come into the office, and you give them a screening test, you can't make them feel better. The only thing you can do is make them feel worse. So we balance both the benefits and the harms of any preventive service.

    Q:Did a concern over cost drive this balancing act?

    V.M.:That was not a big concern. It was more general. … You don't want to do something that doesn't work—that is just a waste of money. More important, it is a waste of time. In a clinical encounter, you don't want to waste any of the limited time you have.

    Q:Why was the recommendation against routine mammography controversial?

    V.M.:The timing of the release coincided with health reform and the election. People were looking for a reason to be upset. … The health care reform bill said that if the USPSTF makes a recommendation with a grade of A or B, that service would be first-dollar covered [by health care providers]. Well, the task force didn't give mammography for women aged 40 to 49 an A or B, so people interpreted it to mean they wouldn't be able to get [insurance] coverage. But that isn't what the recommendation says at all.

    Q:What did you take away from that experience?

    V.M.:We learned that we were suddenly in the public eye, which has dramatically changed how we communicate. We have expanded the transparency of what we do and opportunities for input from the public and from other stakeholders.

    Q:Did you have public comment before?

    V.M.:We did not. … Everything went out for review to all kinds of people who we thought would be interested. Now it is put out on our Web site for anyone who wants to respond. We now invite public comment at the point when we are starting to think about a topic, so the public can say, “Well, you are not asking the right questions.” … It really helps us to understand what people are interested in, what they are concerned about. And other experts may look at an issue and say, “I think you should frame it differently.”

    Screening shocker.

    The task force's decision on mammography upset many groups.


    Q:Did the PSA recommendation turn out to be as controversial as mammography?

    V.M.:In some ways it is probably more controversial. The mammography recommendation itself is not all that exciting. … It says: Think carefully because there are some downsides. … Don't just leap into it. The PSA recommendation says: Don't do it. That has been very controversial with the urologists and with some but not all advocacy organizations. … We all have great hope [that preventive screening will work], and it is pretty painful to have that hope taken away.

    Q:Have task force recommendations caused a change in behavior?

    V.M.:There has been a change in mammography frequency—that has been pretty well studied now over the last couple of years. And there have been a couple of studies looking at the frequency of PSA [tests]. And [both] have gone down a little bit.

    Q:Does it take a long time for recommendations to be acknowledged?

    V.M.:Absolutely. We shouldn't be surprised by this. There are tons and tons of data out there on how long it takes for changes in health care to really take hold in practice. There was a study decades ago that's always quoted that says it takes 18 years to get anything new into practice—that may not be exactly accurate, but it is true that change is hard and it takes a long time.

    Q:There's a bill in Congress mandating that medical specialists be included on USPSTF panels. What do you think of it?

    V.M.:It is important to recognize that … we [at USPSTF] already do have the appropriate specialists on the panel: specialists in primary care and in evaluating science. Our recommendations are addressed to primary care clinicians about people who visit their generalists without specific concerns; these are not people who are going to specialists with a concern. If you put advocates on the panel, all you're doing is asking for advocacy, not science.

    Q:How much should task force work be linked to policy, such as spending decisions?

    V.M.:In many countries—England is a good example—the body that does the type of work we do is directly linked to policy decisions. In this country, that doesn't go as well. … We do not do cost-effectiveness analysis. That is a scientific field in and of itself, and it's very resource-intensive. We don't do that.

    Q:Some say it would be a mistake to link the scientific review and policy decisions because the science would suffer.

    V.M.:That tends to be right. … We don't ignore the fact that there are [financial] costs associated with things, and we particularly consider cost to the individual to be a potential harm, but not in an explicit quantitative way. We do consider the fact that a false-positive test not only ends up requiring in many instances invasive and unpleasant procedures to determine that it was a false positive, but it can also be costly to the individual in time and money. My most recent false-positive mammogram cost me $2000 out of pocket, because insurance only covers the mammogram; it doesn't cover the biopsy. Two thousand dollars is real money. Our purpose is not to save the system money. Our purpose is to improve the health of all Americans.

    Q:Will the task force always be in the middle of controversy?

    V.M.:Probably. And that's OK. Somebody needs to be looking at the things that we [physicians] always do with a critical eye.

  7. Public Health Measures in Disease Prevention

    Organizations and countries have tackled noncommunicable diseases with a variety of public health measures. Science describes some notable examples.

    Vaccines for infectious pathogens, often mandatory, are a widespread method of preventing diseases in a population, but organizations and countries have also tackled noncommunicable diseases with a variety of public health measures. Here are some notable examples.

    C-ing Off Scurvy


    Scurvy, which was recognized as far back as Hippocrates, results from a deficiency of vitamin C and prevents the formation of collagen. Scurvy was once a common problem for those on long marine voyages, killing more than a million sailors according to some estimates, but evidence slowly built that eating citrus fruits and other foods rich in vitamin C could prevent it. Ultimately, Britain's 1867 Merchant Shipping Act would mandate that sailors in the country's Royal Navy or Merchant Navy receive a daily ration of lime or lemon juice to prevent the condition.

    Pass the Salt

    The mineral iodine plays a crucial role in the development of the body and the brain; a deficiency can lead to mental retardation, cretinism, and thyroid problems. Switzerland was the first to introduce iodized salt, in 1922, as a way to help prevent these conditions, and the United States and many other countries would soon adopt the practice.

    A Taxing Effort


    Rates of obesity, heart disease, and diabetes are all increasing worldwide, and many nutritionists lay the blame on eating too much food laden with sugar and fats. Last year, Denmark sought to curb poor nutrition by making certain products more expensive, introducing a tax adjusted to the saturated fat content on products such as butter, milk, cheese, pizza, meat, oil, and processed foods.

    Thwarting Decay


    Cavities, or caries, result when an infection—usually bacterial—demineralizes teeth, but more than a century ago researchers began to explore whether fluoride in water could stymie that process. After a study in a Michigan city showed that fluoridating the water supply reduced tooth decay among residents, U.S. officials backed the prevention strategy in 1951. Water fluoridation would soon become widespread in the United States and many other countries, though some worry about its other health implications or argue it infringes their rights.

    Baby Safeguard

    There's frequently debate about whether a screening method saves lives, but few doubt the effectiveness of one widely used method: the phenylketonuria (PKU) test now given to newborns in many industrialized countries. Often part of an arsenal of other newborn assays, the PKU test checks whether an infant has a toxic buildup of the amino acid phenylalanine, which can lead to mental retardation and other medical problems. If PKU is detected in a newborn, the infant can be given a specialized diet and avoid most health effects.

    Tobacco Warning


    In response to a 1964 report on smoking by the Surgeon General, the United States became the first country to mandate health-hazard warnings for cigarettes and other tobacco products. Other countries have followed suit, and the warnings have recently become even more graphic and aggressive.

    Flour Power

    The addition of folic acid to breads, grains, flour, and other food products in many industrialized countries has been credited with reducing the number of babies born with neural tube defects. The U.S. Food and Drug Administration announced in 1996 that it would begin requiring folic acid fortification in certain foods, and a few other countries have taken the same action. Similarly, niacin has been voluntarily added to enriched flour in some countries to help ward off pellagra, the sometimes fatal disease caused by a B vitamin deficiency.

  8. Will an Aspirin a Day Keep Cancer Away?

    1. Jocelyn Kaiser

    Data suggesting that regular aspirin use lowers cancer risk has accumulated to the point where some argue that it's time to recommend that many more people take the drug.

    In the late 1970s, a surgeon in Melbourne, Australia, wanted to figure out why his country had a relatively high rate of colorectal cancer. After he and colleagues interviewed more than 700 cancer patients and a comparable number of healthy people, they reported in 1987 and 1988 that Australians' penchant for beer, fatty foods, and red meat all seemed to predispose them to the disease. The researchers also found a surprising protective factor: People who regularly used aspirin were 40% less likely to develop colorectal cancer than those who didn't take the drug.


    Aspirin may block cancer as well as vascular disease.


    That first hint that the age-old headache remedy also blocks intestinal tumors helped spur a wave of research in animals and clinical trials that established that aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) protect against colon cancer. And now, 2 decades later, aspirin is generating new excitement among cancer researchers. A series of studies from the United Kingdom in the last 2 years has offered the first evidence from placebo-controlled clinical trials that regularly taking low doses of aspirin wards off other types of cancer as well.

    The studies, which tallied cancer cases among people who had been taking aspirin for years to prevent vascular events such as heart attack and stroke, found that death rates from several tumor types were as much as 37% lower. And even in the people who developed a cancer, taking aspirin seemed to slow the spread of tumors to other parts of the body. “It's just about the first proof of principle that a simple compound of any kind can reduce the risk of several cancers,” says lead researcher Peter Rothwell of the University of Oxford in the United Kingdom.

    These reports have raised the tantalizing possibility that aspirin could serve as the first anticancer drug for the general population. “It reshapes the debate about the risks and benefits of aspirin for cancer prevention,” says colorectal cancer researcher Andrew Chan of Massachusetts General Hospital in Boston.

    Because aspirin can cause stomach upset and dangerous internal bleeding, U.S. guidelines now recommend that only people at elevated risk for heart disease or stroke take low doses of the medicine, typically 81 milligrams a day. But Chan and others suggest that medical societies and policymakers should also consider aspirin's general cancer-fighting effects. Rothwell, who is 48, is so convinced by his team's data, for example, that he's begun taking aspirin daily even though he has no risk factors for vascular disease.

    The new British aspirin studies are also fueling basic research on NSAIDs to ward off cancer, a field that lost momentum in the past decade when one NSAID, Vioxx, was pulled off the market because of safety concerns. Partly because of the U.K. results, U.S. National Cancer Institute (NCI) Director Harold Varmus last year added to his list of 24 “Provocative Questions” one that asks what is the mechanism by which aspirin and other NSAIDs protect against cancer (see sidebar, p. 1472). NCI hopes the attempt to resolve the question—there are several competing theories—will lead to next-generation anticancer drugs and biomarkers showing who will respond to them.

    But some cancer researchers say health policymakers needn't wait for a better aspirin and should advocate wider use of the current one. “This is a really extraordinary opportunity if everything bears out, because you have a drug that costs a penny a pill at a low dose, that can prevent the two major causes of death in the Western world,” says epidemiologist Michael Thun of the American Cancer Society in Atlanta.


    Thun's optimism is the latest high in the up-and-down story of NSAIDs as a cancer preventive. Aspirin and some other NSAIDs first bore out their promise in trials published starting in 2000 among people who had had precancerous colon polyps removed and others genetically prone to colorectal cancer. The drugs protected them from polyps and premalignant tumors that precede full-blown cancer. Such people are now sometimes advised by their doctors to take NSAIDs as an adjunct to surgery to prevent polyps from recurring.

    Although epidemiological evidence has suggested that aspirin could have broader anticancer effects, those results aren't conclusive. They come from studies in which people answered questions about their past use of medications—a design prone to bias in part because memories aren't reliable. And hopes for aspirin fell in 2005 when a huge prospective study—a randomized controlled trial called the Women's Health Study (WHS)—failed to show a reduction in the incidence of cancer in nearly 40,000 women who took low-dose aspirin every other day for 10 years.

    The field of NSAIDs for cancer prevention also suffered a black eye when two arthritis drugs developed to avoid the side effects of aspirin, the COX-2 inhibitors Vioxx and Celebrex, were tested in trials to prevent colon polyps. In one large trial, Vioxx cut the risk of polyps but raised the chances of heart attack so much that risk arguably outweighed the cancer benefit. Vioxx was pulled off the market in 2004 and Celebrex, although still used for preventing colorectal cancer in people at high risk of such disease, now carries a “black box” warning label.

    The pendulum began to swing back in favor of aspirin, however, when Rothwell, a neurologist, noticed that fewer overall cancers had occurred among patients in the treatment arm of randomized trials launched in the 1980s to test aspirin as a way to prevent stroke. Amassing details on the cancers from patients' paper health records and U.K. health databases, his team initially confirmed aspirin's ability to ward off colorectal cancers, reporting in 2007 that there were 24% fewer cases and 35% fewer deaths in the aspirin group after several years. Then in late 2010, they reported that patients taking aspirin at any dose daily for at least 5 years cut by 21% the long-term risk of dying from colorectal, gastrointestinal, esophageal, stomach, pancreatic, brain, lung, and prostate cancers.

    Rothwell's group expanded on these results in three papers published in The Lancet and The Lancet Oncology this spring. One, a meta-analysis of 51 randomized trials in which aspirin was taken daily, found 37% fewer deaths from cancers after 5 years. (The study came with a large caveat: It excluded WHS and an earlier trial that found no benefit, the Physicians' Health Study, because participants in each took aspirin only every other day.) This meta-analysis also found that while the aspirin group had more stomach bleeds, these incidents were not fatal—people recovered—and the bleeding risk went down after several years on aspirin. Another paper found that people on aspirin who developed cancer were 36% less likely to have tumors that had spread. A third paper found a “remarkable consistency” in the drop in cancers among aspirin users in epidemiologic studies and clinical trials, Rothwell says.


    Peter Rothwell's cancer studies convinced him to take a daily aspirin.


    While these studies weren't designed specifically to test aspirin against cancer, some researchers say that because so many people now take aspirin off-label it would be difficult to conduct better trials. The Rothwell studies are “probably the best evidence we'll ever have on this topic,” Chan says.

    Weighing risks

    Chan is part of an international panel on cancer prevention that, in response to the Rothwell studies, plans to update its stance on aspirin published 3 years ago. The group's leader, epidemiologist Jack Cuzick of Queen Mary, University of London expects the panel may suggest that people take low doses of aspirin daily starting around age 50 and stopping by age 70, when the risk of internal bleeding rises. The group may also discuss whether doctors should screen patients for the ulcer-causing Helicobacter pylori bacterium, treating those who test positive with antibiotics before putting them on aspirin, to reduce the risk of bleeds.

    Some U.S. researchers also suggest that it's time for the U.S. Preventive Services Task Force (see p. 1468) to update its guidelines on the risks and benefits of daily aspirin use. The group had endorsed its preventive prowess for heart attack and stroke but discounted its anticancer effects. The potential to protect against both cancer and heart disease could tip the balance toward recommending aspirin for many more healthy adults, Thun says.

    Others are more cautious about recommending broad use of aspirin to ward off cancer. “In 2012, gastroenterologists still get called to the emergency room for bleeds” caused by the drug, says cancer prevention researcher Andrew Dannenberg of Cornell University. Colorectal cancer researcher Sanford Markowitz of Case Western Reserve University in Cleveland, Ohio, points to studies suggesting that only people with a particular genetic profile will see their cancer risk go down if they take aspirin. “I would want more data on who benefits and who does not,” Markowitz says.

    Cancer prevention researcher Raymond Dubois of the MD Anderson Cancer Center in Houston, Texas, is also wary. “Initially we thought we could put aspirin in the drinking water. That's not the case,” he says. “Where this field is going is towards a more personalized approach.”

    The picture may become clearer soon when WHS reports on longer-term effects of aspirin on cancer risk. Their next paper “will be crucial,” Rothwell says. And even some on the pro-aspirin side urge caution. “We don't want to mess this up,” Thun says.

  9. Wondering How the Wonder Drug Works

    1. Jocelyn Kaiser

    The latest clinical studies linking low-dose aspirin use with less cancer suggest there's no need to improve upon this 113-year-old workhorse drug.

    How does taking aspirin ward off cancer? Researchers still don't understand the mechanism, a lack of knowledge that threatens to frustrate development of better cancer prevention agents. But some say the latest clinical studies linking low-dose aspirin use with less cancer (see main story, p. 1471) suggest there's no need to improve upon this 113-year-old workhorse drug.

    Among its many known effects, aspirin, or acetylsalicylic acid, inhibits two forms of enzymes known as cyclooxygenases (COX) that convert arachidonic acid into lipids called prostaglandins. Prostaglandins made by COX-1 protect the stomach lining, while those made by COX-2 are involved in inflammation. Aspirin's inhibitor effects on COX-1 seem to explain why the medicine can upset stomachs and trigger internal bleeding. Many researchers have concluded that aspirin prevents cancer mainly by blocking the activity of COX-2. That's because the same inflammation-driven responses that help tissue recovery from wound injury—cell division, blood vessel formation, and suppression of programmed cell death, for example—may also help tumors grow.


    Several lines of evidence implicate COX-2 in cancer induction. The enzyme is overproduced in many cancer types; mice lacking its gene are less prone to colon cancer; and trials of nonsteroidal anti-inflammatory drugs (NSAIDs) that target only COX-2 protected against precancerous colon polyps in people at high risk.

    Reducing inflammation via COX-2 probably isn't the only way aspirin prevents cancer, however. “We are as a field getting down to some of the mechanisms, but it's very complicated,” says Raymond Dubois of the MD Anderson Cancer Center in Houston, Texas. A decade ago, researchers found that aspirin can block production of a protein called NF-κB that protects cells from early death. Although the studies were done in the test tube at aspirin doses much higher than those in the bloodstream, the NF-κB hypothesis remains on the table—along with more than a dozen possible mechanisms—from inhibiting various cell growth pathways to targeting cancer stem cells. “There are a number of very different, divergent ideas,” says Asad Umar of the National Cancer Institute's Division of Cancer Prevention in Bethesda, Maryland.

    Some experts say new clinical studies of low-dose aspirin and cancer suggest that COX-2 isn't directly involved at all. That's because at low doses, the drug doesn't block COX-2 but still impairs platelets, the small cell fragments in blood that help form clots, via the COX-1 pathway. Studies suggest that platelets blunt the immune attack on cancer cells traveling in blood and produce growth factors that help them take root in a new place, notes University of Pennsylvania pharmacologist Garrett FitzGerald. Some experiments suggest that activated platelets can also stimulate the COX-2 pathway in adjacent cells, which would explain how aspirin, by damping COX-2 at the site of an injury, could block the early stages of colorectal cancer, says Carlo Patrono, a pharmacologist at the Catholic University in Rome, Italy.

    Efforts to make an alternative to standard aspirin haven't yet panned out. Several drugs that target only COX-2, notably Vioxx and Celebrex, unacceptably raised heart attack risk, for example. And a version of acetylsalicylic acid containing a chemical group called nitric oxide that was supposed to reduce side effects failed to gain regulatory approval. Some researchers are combining aspirin with other compounds such as a lipid to reduce stomach upset. But these are years from the clinic. For now, “I don't think a better aspirin is the issue,” but rather figuring out which individuals stand to benefit from it most, FitzGerald says.

  10. Tackling America's Eating Habits, One Store at a Time

    1. Jennifer Couzin-Frankel

    Several initiatives are evaluating if easing access to healthy food will change how Americans eat—and reduce obesity around the country.

    Philadelphia story.

    With a push from a local nonprofit, The Food Trust, and a windfall of federal funding, efforts are underway to boost healthy offerings at small grocers around the city.


    PHILADELPHIA, PENNSYLVANIA—The food market Clara Santos runs in South Philadelphia is less than 5 kilometers from the city's majestic art museum. Driving there, polished brick townhouses and trendy eateries with names like Caffeination and The Belgian Café give way to stretches of modest row houses, abandoned lots, and the occasional corner store advertising massive sandwiches called hoagies. Santos, who emigrated from the Dominican Republic, lives not far from the Olivares Food Market she took over 4 years ago. Graffiti marks its outer walls, but the shop, on a quiet block sandwiched between two city schools, is tidy inside. Children stop in frequently for soda and candy after classes let out.

    Santos's store is one of 642 data points in an unusual urban experiment. Eight years ago, a local nonprofit called The Food Trust began studying whether bringing healthy, affordable food to corner stores like hers could change eating habits among the city's economically disadvantaged residents. The program started small. Then in 2010, the Healthy Corner Store Initiative rapidly expanded after partnering with the Department of Public Health here, which had just received a windfall: $15 million to help prevent obesity, part of $373 million from the federal stimulus package earmarked for health and wellness efforts around the country. Santos joined the project last year along with hundreds of other convenience store owners. Among other support, she received a display refrigerator where she showcases yogurt, precut watermelon, carrots, apples, and other fruits and vegetables, along with green bins for produce such as onions and plantains. Why not give the program a try, Santos says she thought: “Maybe we'll help the community.”

    Like Santos and those at The Food Trust, more and more people are trying to change the landscape of food in America. And change is desperately needed. More than one-third of U.S. adults are obese, as are about 17% of children ages 2 and up. In 2008, researchers estimated that obesity cost the nation a staggering $147 billion in medical costs.

    Many paths lead to obesity, and the lack of access to healthy foods is thought to be just one of them—but for those on the front lines, it seems among the easiest and cheapest to modify. The strategy is also getting a boost from first lady Michelle Obama, whose plan to combat childhood obesity includes the elimination of “food deserts,” defined as low-income communities that are a significant distance from a full-fledged grocery store, though the specifics vary depending on whether the neighborhoods are urban or rural, among other factors.

    Swapping food deserts for stores boasting fresh produce and other healthy foods—and using varied strategies in hopes of coaxing locals to buy them—comes with two questions. First, does promoting these foods change eating habits over the long haul? And second, does this, in turn, help fight obesity? Marketing bananas, demonstrating how to use cabbage in meals, and putting more boxes of wholesome cereals at eye level all sound like sensible practices that should help people lose weight or keep it off, but until recently, more effort has gone into initiating such interventions than scientifically measuring whether they matter. People “have an intuitive feel about the value and worth of this,” since individuals cannot improve their eating habits and potentially lose weight if the food isn't available to them, says Allison Karpyn, the director of research and evaluation at The Food Trust. “The mandate from policymakers was, ‘These communities need stores, they need revitalized neighborhoods.’ It wasn't, ‘We want to measure their BMI.’”


    This U.K. supermarket, which opened in an impoverished area in 2000, was studied for its impact on eating habits.


    Evolving tactics

    In the early days of food-desert research, it was hoped that simply plunking down a well-stocked supermarket where there wasn't one could change eating habits. One of the first people to test this was Neil Wrigley, an economic geographer and urban planner at the University of Southampton in the United Kingdom. Through his planning work, Wrigley was well-connected to the retail industry, and in 1999 he learned that a sizable supermarket would soon open in an impoverished area of Leeds.

    The neighborhood had high crime rates and many very young mothers. It was, Wrigley says, “isolated from the mainstream of economic life.” From this community, Wrigley recruited 1009 households to help him examine how eating habits changed after the supermarket opened. Tracking eating habits for a week, 5 months before and again 7 months after the supermarket opened, Wrigley determined that the new supermarket did indeed influence food choices, but its impact was slight and variable.

    Taking together all 615 households that stuck with the study, there was no measurable difference in fruit and vegetable consumption. But when the researchers looked at only the several hundred households that switched to shopping at the new store, there was a modest change: They added about a quarter-serving of produce to their diets, boosting the total to 2.89 servings—still far below the recommendations at the time of five servings a day. “We weren't expecting a big impact from improving availability, we just wanted to see whether there was any impact,” says Wrigley, who called the results “heartening.”

    Wrigley's results suggested that a new store on its own has only so much power. Some consumers avoided the Leeds supermarket because they worried they'd be tempted by its rich offerings and would waste money. Furthermore, “many of these 21-year-old mothers had no experience in cooking at all,” Wrigley says.

    Another reason a new store has limited influence is that nearly everyone, no matter how they eat, is accustomed to buying roughly the same foods and preparing roughly the same dishes week after week. “You have to change patterns that have been ingrained over time,” says Helen Lee, who recently moved from the Public Policy Institute of California in San Francisco to the social policy research organization MDRC in Oakland, California.

    Lee studied how proximity to grocery stores affected childhood obesity in about 3200 communities around the country. The result? “What children had access to in their residential environments didn't predict who became overweight or who stayed overweight,” she says. In general, evidence suggesting that people eat better when there's healthy food nearby “is really mixed,” says Lee, who worries that eliminating food deserts in the absence of broader structural changes to combat poverty, such as educational reform and job training, could be a waste of precious dollars.

    Against this uncertain backdrop are widespread efforts to promote access to healthy foods among the poor. In both New York City and Philadelphia, residents who use $5 worth of food stamps at a farmer's market receive $2 more to spend on fresh produce there.

    In New York City, the Shop Healthy NYC initiative is, among other things, encouraging owners of more than 1000 of small corner stores called bodegas to stock produce and other healthier foods, such as low-fat milk. But tracing what people are actually buying in bodegas hasn't panned out. “The majority don't have electronic cash registers” and don't provide receipts, says Sabrina Baronberg, who helps oversee the program at the city's Department of Health and Mental Hygiene. “We've tried a variety of mechanisms. … It's very difficult to track sales.”

    The push for change despite limited data has divided public health experts. On the one hand, many say that it's hard to see a downside to offering more fruits and vegetables, low-sodium products, and low-fat dairy options to disadvantaged communities. On the other, with limited public health money, Lee, Karpyn, and others say, it makes sense to understand which strategies work best, rather than implementing a hodgepodge that may or may not make a difference. “I wonder if we're going about it the wrong way,” Lee says, “if we're putting the intervention before the science.”

    Selling the good.

    Researchers and others are experimenting with marketing strategies to sell produce and other healthy foods, and steer patrons from unhealthy choices.



    In neighborhoods dotting San Diego County, Guadalupe Ayala is trying to put science first. Ayala, a public health researcher at San Diego State University in California, focuses on modifying behaviors to prevent obesity and other chronic health conditions. Currently, she's working with 18 small-to-medium-sized grocery stores whose shoppers are mainly Latino. Nine of the stores are left alone. In the other nine, Ayala intervenes by helping the owners offer healthier foods: by providing, for example, a salad bar for precut vegetables (which many Mexicans like to eat, she says), or exploring how ingredients in prepared foods can be modified to make them healthier. The researchers are also providing marketing materials to highlight healthy foods. Thanks to their small size and the immigrant community they serve, the store's staff members know many of their shoppers by name—leading Ayala to suspect that they might have sway over what customers buy. With this in mind, employees are trained “to do suggestive selling to promote healthier foods.”

    To measure the outcome of the various interventions, Ayala and her colleagues are recruiting 396 customers—22 for each store—and tracking their eating habits for a year. The researchers are also studying what goes on in the stores: Do they sell more healthy foods? Do they allocate more space to such food? Do they use any marketing strategies beyond what Ayala suggests? To verify that customers are eating the fresh produce they buy, Ayala had planned to gather blood samples from 25% of participants and look at levels of carotenoids, a component in fruits and vegetables. But the grant, which is funded by the U.S. National Cancer Institute, was reduced and that side project was eliminated. Still, Ayala has an impressive $2.75 million for the effort—a sign of how expensive it is to probe these questions on even a small scale.

    Another challenge for researchers like Ayala is keeping healthy foods affordable. She and her colleagues are keenly aware that if the foods they highlight aren't roughly the same cost or cheaper than what they aim to replace, interventions are unlikely to work. This often means focusing on less expensive produce, such as tomatoes and zucchini. Or it might mean expanding the number of stores that belong to the federal government's supplemental nutrition program for women and young children called WIC. Not every grocer that wants to can join WIC because of limited state resources to certify and monitor the stores. Those that do belong benefit from a guaranteed customer base. “We found that [participation in] WIC was the overriding determinant in whether a store had fresh fruits and vegetables, low-fat milk, [and] whole grains,” says Ann Ferris, who directs the University of Connecticut's Center for Public Health and Health Policy in East Hartford. She has a paper coming out that backs this up.

    To sell more healthy foods in Philadelphia, The Food Trust and its collaborators also rely on strategies used with great success to move junk food off store shelves. “If you put all the low-sodium goods together and put marketing around it and make it like a flashing beacon around the store, you'll attract attention,” says Brianna Sandoval, who is overseeing the corner store initiative.

    With colleagues at nearby Temple University and the University of Pennsylvania, The Food Trust is testing this approach in eight large grocery stores, most of them in Philadelphia. Four of the stores serve as controls, while in four others the researchers altered product displays in an effort to encourage healthier purchases. “It's a stealth intervention,” says Gary Foster, who's helping lead the study and directs the Center for Obesity Research and Education at Temple. “Where the whole milk used to be, the skim is.” More boxes of Cheerios are visible, along with more low-calorie soda; healthier frozen meals are at eye level. Still, Foster concedes that the approach is unlikely to radically change shopping habits. “In the scheme of things, it's a pretty weak intervention,” he says. But because it costs stores little, it's also sustainable.

    As this store-by-store research progresses, there are glimmers that changing eating habits, at least a little, is doable. Interventions in San Diego, Baltimore, Philadelphia, and beyond suggest that customers can be coaxed into buying healthier foods. But even if this works on a grander scale, across urban and rural areas—and no one knows yet if it will—can such changes make a meaningful dent in obesity? “There's an assumption built in here that nobody ever articulates,” says Kelly Brownell, director of the Rudd Center for Food Policy & Obesity at Yale University. The assumption is that healthy foods sit on one end of a seesaw, with unhealthy foods on the other—and thus that eating more broccoli and Greek yogurt means ingesting fewer McDonald's hamburgers or liters of soda. There's no evidence to support this, however, he says.

    Brownell, whose favored strategy is making it more difficult to find and afford unhealthy foods, still believes that access to healthy food matters. More fruits and vegetables reduce cancer and heart attacks, and communities deserve food choice. “If I didn't study obesity, but I studied cancer or heart disease, I'd be very happy about” these projects, he says. “But we can't necessarily expect [them] to help the nation's obesity problem.”

  11. Uncertain Verdict as Vitamin D Goes On Trial

    1. Kai Kupferschmidt

    Boosting levels of vitamin D with supplements has been touted to prevent diseases, but many scientists say only clinical trials now in the works can confirm such hopes.

    Ounce of prevention.

    Cod-liver oil has been given as preventative medicine for decades (left, British children in 1938 are presumably getting their spoonful). Now scientists are amassing tens of thousands of volunteers to test the preventive power of one of its ingredients: vitamin D.


    In 1848, doctors at the hospital for Consumption and Diseases of the Chest in London undertook one of the world's first clinical trials. More than 1000 patients with tuberculosis (TB) were either just cared for, as no effective treatment was known, or were also given a spoonful of cod-liver oil three times a day. Nineteen percent of patients on cod-liver oil deteriorated or died, compared to 33% in the control group.

    Before antibiotics became available in the mid-20th century, many TB patients were also sent to sanatoriums in Switzerland or other countries. Lying in their beds, they were wheeled out into the sun for phototherapy. Looking back, says Adrian Martineau, an immunologist at Barts and The London School of Medicine and Dentistry in London, the two experimental therapies had something in common: vitamin D, which wasn't discovered until 1922.

    Unlike other vitamins, the human body produces most of its vitamin D itself—with the help of sunshine. In the skin, a precursor molecule called 7-dehydrocholesterol is turned into vitamin D3 by UV light. Ninety percent of vitamin D circulating in the human body is produced that way. Only 10% comes from food, in the United States and Canada mostly from milk, which is fortified with the vitamin in those countries. It is also naturally abundant in some foods including fatty fish, sun-dried mushrooms—and cod-liver oil.

    Martineau has studied the connection between TB and vitamin D for years and has become convinced that the compound can not only help treat TB but also prevent it. He is part of a vocal camp of scientists who praise the powers of vitamin D and see it as something of a cure-all—or rather a prevent-all. In addition to its well-established benefits for bone health, they say vitamin D may—with little or no side effects—be able to ward off colds and other infections and cut the risk of asthma, diabetes, cancer, heart disease, and a slew of other chronic diseases.

    Some of these scientists, such as Michael Holick, an endocrinologist at Boston University School of Medicine and a veteran of vitamin D studies, advocate fortifying more foods with the vitamin and advising people to take supplements and get more sun exposure. “Even if only one of these diseases turns out to be prevented by vitamin D, it is worth it,” he says. The public certainly seems to buy that argument. In the United States, sales of vitamin D supplements have increased from $50 million in 2005 to $600 million in 2011, according to the Nutrition Business Journal. Ninety years after it was discovered, vitamin D seems to be enjoying its moment in the sun.

    But other researchers warn that the benefits of vitamin D are far from proven. They also caution that its widespread use as a supplement could do more harm than good, as trials of other vitamins have shown. Even a believer like Julian Peto, an epidemiologist at the London School of Hygiene and Tropical Medicine, cautions, “You have got to be very certain. Mass medication is not something you embark on lightly.” He adds: “What we know comes mainly from observational studies.”

    In the next few years, however, the long-standing vitamin D debate may finally be put to rest. In a number of large clinical trials, tens of thousands of people around the world will take a supplement or placebo pills in an effort to pin down the health benefits of the sunshine vitamin.

    A body of evidence

    Vitamin D was first recognized for its role in bone health. It helps the body absorb calcium, and children who do not get enough of it can develop rickets, a bone-softening disease. But low vitamin D levels have also been implicated in infectious diseases. For instance, patients with TB tend to have lower vitamin D levels, and Martineau points to studies showing that the compound helps immune cells called macrophages kill the mycobacterium responsible for TB, as well as suppress the secretion of enzymes the pathogen uses to degrade lung tissue.

    In 2010, a randomized trial in 334 Japanese schoolchildren found that those taking vitamin D supplements were less likely to suffer from an influenza infection. And in August, scientists from Harvard Medical School in Boston reported in Pediatrics that Mongolian schoolchildren whose milk was fortified with vitamin D had half the risk of catching a cold compared to those drinking unfortified milk. It is perfectly plausible that lower vitamin D levels in winter might be the reason colds predominately circulate then, Peto says.

    Proponents of the sunshine vitamin have also amassed a variety of data suggesting it wards off asthma, diabetes, stroke, multiple sclerosis, and cognitive decline. And a body of evidence indicates vitamin D could cut the risk of cancer and cardiovascular disease dramatically, they argue. For colorectal and breast cancer alone, raising vitamin D levels on a population level could prevent more than 100,000 cases each year and cut deaths from these diseases by three-fourths in the United States and Canada, a paper published in the Annals of Epidemiology in 2009 calculated.

    Vital sunshine.

    UV rays striking the skin convert the molecule 7-dehydrocholesterol to an inactive form of vitamin D3. It is then converted first in the liver and then the kidneys to 1,25-dihydroxyvitamin D3, the active form of the vitamin.


    One comprehensive review of the vitamin D literature, a meta-analysis published in 2011 by the Cochrane Collaboration, concluded that vitamin D3 supplementation (but not other forms of the vitamin) reduced overall mortality by about 6% among the more than 90,000 people in the 50 studies examined. “That is not overwhelming, but it is borderline significant,” says Robert Scragg, a vitamin D researcher at the University of Auckland in New Zealand.

    Many vitamin D enthusiasts point to evolution to bolster their case. Dark skin protects skin cells from UV damage, but it also reduces the amount of vitamin D that is produced; African-Americans in the United States generally have lower levels of vitamin D in the blood than the rest of the population. “The strongest single bit of evidence [that more vitamin D is good for a person] is that humans turned white when they moved north,” Peto says. “That suggests low vitamin D levels must have had [a negative] effect on survival.”

    Mass medication

    However, some veteran vitamin researchers caution that other vitamins have been linked to a broad range of health benefits, only to have the evidence crumble upon closer examination. In the 1990s, for example, observational studies suggested that antioxidants such as beta carotene (a precursor of vitamin A) could shield the body from the cancer-causing compounds in tobacco and other harmful substances. But in 1994, a prospective clinical trial with nearly 30,000 smokers in Finland concluded that those who had taken beta carotene supplements were actually 18% more likely to develop lung cancer and 8% more likely to die during the trial. Two years later, a U.S. study examining vitamin A supplements in smokers and asbestos workers was stopped early because there were 28% more lung cancers and 17% more deaths in the group receiving vitamin A than among the untreated.

    Another antioxidant, vitamin E, was also touted as a cancer killer. But in 2008, a cancer-prevention trial evaluating vitamin E and selenium supplementation was stopped because participants taking vitamin E had become more likely to get prostate cancer. The risk difference then was not statistically significant, but follow-up data published late last year showed a significant increase of 17% compared with the control group.

    Some predict that history is about to repeat itself. “I think vitamin D is going the way of these other treatments,” says Andrew Grey, a researcher at the University of Auckland. Low levels of vitamin D might simply be a marker of bad health rather than the cause of it, he suggests: “Almost always the levels are lower in patients who are sicker, but that could be because they exercise less and do not go outside so much.” Another confounding factor: Vitamin D is fat-soluble, so obese patients also tend to have lower levels of circulating vitamin D.

    JoAnn Manson, an endocrinologist at Harvard Medical School, agrees that once again enthusiasm for a vitamin is outpacing the evidence: “There are many reasons that low vitamin D levels might be linked to these chronic diseases. Correlation does not prove causation.”

    Other groups reviewing vitamin D data haven't been as impressed as the Cochrane group. After sifting through hundreds of studies, a panel convened by the Institute of Medicine (IOM) concluded in 2010 that vitamin D was important for bone health, but that evidence did not support other benefits from vitamin D intake.

    Difficult dosing


    Tackling another contentious issue at the heart of the vitamin D debate, the IOM report also recommended an adequate blood level of the vitamin: 50 nmol/l. “Some people with malabsorption may need higher levels, but for the healthy population 50 nmol per liter is certainly enough,” says Clifford Rosen, a bone-health expert at Maine Medical Center Research Institute in Scarborough, who was on the panel. The report also pointed out that most people in the United States reach that level through diet and sun exposure alone.

    The strong vitamin D proponents, as well as other scientists, say the IOM threshold is too low and hark back to prehistoric times to make their point. They argue that as humans started wearing clothes, developed sunscreens, and began spending many hours indoors, they cut themselves off from the level of vitamin D they used to have. Dutch scientists published a study earlier this year examining vitamin D levels in two tribes in Tanzania. Living close to the equator, following a hunter-gatherer-like lifestyle, and not using sunscreen, the Maasai and Hazabe peoples had a mean serum concentration of 115 nmol/l. “That is probably where we all should be,” says Holick, who takes supplement pills to keep his vitamin D level between 100 and 150 nmol per liter.

    Others don't aim as high, at least for keeping the skeleton strong—the best studied aspect of vitamin D prevention science. “To ensure good bone health in everyone, you need to aim for a level of 75 nmol per liter,” says Michael Amling of the University Medical Center Hamburg-Eppendorf in Germany.

    In a 2010 paper, Amling examined the bones and vitamin D levels of 675 people who had died in car accidents or of other unnatural causes. Seven of 82 people with a level above 50 nmol/l had weak bones. “That means almost 10% of the people with a serum level above this threshold have weak bones,” Amling says.

    But the IOM panel, which had set itself the goal of allowing no more than 2.5% of the population to be at risk of brittle bones, used a different number: It divided the seven bodies with high vitamin D but low bone health by the total number of bodies: 675. “That was a grave mathematical mistake,” Amling says.

    Rosen warns that having higher blood levels of vitamin D could be harmful. “I can actually live with 75 nmol per liter, but above that I am a little concerned,” he says.

    He and others cite a 2010 Australian study in which women aged 70 years or older were given a megadose of 500,000 international units (IUs) once a year. Vitamin D levels in their blood shot up to an average of 120 nmol/l, but these participants also fell and fractured their bones more often than those in the placebo group, the scientists reported.

    Proponents of vitamin D argue that such a megadose is unphysiological and that the study is a special case that should not be weighed too heavily in any risk-benefit analysis. Rosen disagrees: “There is very little randomized clinical trial data that gets up to these levels, and there is just no evidence that it actually protects against skeletal problems or other diseases.”

    Interjecting another note of caution, a paper published in the American Journal of Cardiology in January 2012 showed that vitamin D in the blood reduces inflammation, measured by a protein called C-reactive protein (CRP)—until the vitamin's level reaches 50 nmol/l. Above that mark, the relationship reverses and more vitamin D increases CRP levels again. The authors concluded that supplementation with vitamin D to reduce inflammation may be beneficial only in those with low serum concentrations of the vitamin.

    Proving prevention

    With the intent of resolving the usefulness of vitamin D, several investigators are launching large-scale trials to examine the benefits of vitamin D in a number of chronic diseases. In the VITAL study Harvard's Manson leads, for example, 20,000 healthy people in the United States will receive either 2000 IUs of vitamin D a day or a placebo for 5 years. That should be enough to raise blood levels of vitamin D to 75 nmol/l or more in nearly all participants, she says. The trial will look at health outcomes as diverse as stroke, diabetes, cardiovascular disease, and cancer. The first participants are already taking their pills, and the last ones should be recruited by the end of the year, Manson says. Similar studies are starting in Finland, New Zealand, and Switzerland; another one in the United Kingdom is in the pipeline (see table).

    Such prevention trials are challenging—and may not ultimately satisfy everyone. They must have large numbers of subjects and run for a long time, because enough participants need to develop a disease to see a difference between the two groups. That makes them very costly; the VITAL study, funded by the U.S. National Institutes of Health, will cost about $30 million. Compliance is also an issue, because healthy people taking part in a trial of vitamin D may be more likely to forget to take the pills than sick patients in a drug trial—especially because there is no doctor administering the treatment in a clinic. In the VITAL study, participants will receive their pills in the mail once a month; in the Finnish study, the volunteers will be mailed 400 pills once a year. If many people forget to take their pills, that would make it harder to detect a difference between the treatment and control groups.

    There is another respect in which the vitamin D trials differ from most other randomized clinical trials: Normally, the placebo group receives none of the compound being investigated, but participants in the placebo group of a vitamin D trial will still produce the vitamin in their skin and consume it with their food. That narrows the gap between the two groups. In addition, in all the ongoing trials, participants will be allowed to take low-dosed vitamin D supplements if they were already taking them. Holick sees that as a fatal flaw in the VITAL study and others: “They are essentially comparing 800 IUs a day with 2000 IUs.” The trial should have given the treatment group 4000-IU supplements to see a clear difference between it and the “control” group, he argues. But Manson points out that participants in both groups are allowed to take supplements. “The difference remains 2000 IUs,” she says.

    The double-blind Finnish study, which will start in a few months, will divide participants into three groups of 6000 that will take either a 1600-IU vitamin D supplement daily, 3200 IUs, or a placebo. And in the study in New Zealand, which in 2017 could be the first to report results, participants will take 100,000 IUs or a placebo once a month.

    Even these large studies may not be definitive enough on their own to settle the vitamin D issue, says Scragg, who heads the New Zealand study. He cites recent evidence suggesting that vitamin D may only be beneficial in those with low initial levels of the vitamin. That means proof of the effectiveness of supplementation may only come from pooling the various studies, he says: “Then you could segment people into various vitamin D ranges based on baseline levels and see whether it has an effect or not.”

    Until those data are in, and maybe even afterward, scientists will likely keep on arguing, Rosen says. Evidence does not matter to many people when it comes to vitamin D, he maintains: “It is a religion. People really believe this stuff works.”

  12. Chronic Disease Vaccines Need Shot in the Arm

    1. Bijal Trivedi*

    Whether vaccines to prevent obesity, asthma, smoking-related illnesses, and other chronic diseases will ever work remains an open question.

    In July, global headlines proclaimed that a “flab jab” was imminent, an obesity vaccine that would allow consumption of endless fast and fatty foods without punishing weight gain. The proof: Mice that were injected with a vaccine targeting the hormone somatostatin gorged on a high-fat diet with significantly less weight gain than those given a sham injection. “Thousands of people contacted us volunteering for clinical trials. Everyone from mothers wanting to lose baby fat to weight lifters in Germany,” says vaccinologist Keith Haffer of small, South Dakota–based Braasch Biotech, who led the rodent study.


    With funding interest from several South American companies, Braasch Biotech does plan to begin human clinical trials of its somatostatin vaccine late in 2013. Hold the extra cheese on that large sausage pizza, however. It's difficult enough to develop and obtain approval for a traditional vaccine against a bacterium or virus, let alone create one that rouses the immune system to target molecules that drive a chronic disease such as obesity. Indeed, potential vaccines for hypertension, asthma, Alzheimer's disease, obesity, and smoking (because it is a risk factor for heart disease, cancer, stroke, and more) have all been hyped for their promise in recent years and then suffered high-profile failures.

    In 2002, for example, a vaccine that raised antibodies to the β-amyloid protein that accumulates in the brains of people with Alzheimer's disease suffered a scary setback when 6% (18 of 298) of the clinical trial subjects receiving the AN1792 vaccine developed a severe brain inflammation. And Nabi Biopharmaceuticals's nicotine vaccine, designed to suck the high out of smoking, failed in a Phase III trial last year. Switzerland-based Cytos Biotechnology also attempted vaccines for smoking, as well as hypertension and type 2 diabetes, and though its researchers made progress, the company ran out of funding in 2011 and abandoned most of those efforts.

    Vaccine developers also face a “psychosocial” problem, says Kim Janda, a chemist at the Scripps Research Institute in San Diego, California, who has worked on vaccines for obesity, smoking, and addictive drugs for the past 30 years. “In large part, society still views addiction or even obesity as a moral failure rather than a chronic disease.” It's difficult to persuade drug companies and the general population to invest in treating something they view as a failure of willpower with an intervention like a vaccine, Janda says.

    Mite-y vaccine.

    Dust mites such as Dermatophagoides farinae (pictured) are a trigger of allergies and asthma, prompting efforts to immunize people against one of their proteins.


    But he isn't giving up and neither are others. “If you can find a target that is the underlying cause” of an illness, Janda says, “then you can develop a vaccine for its treatment.” There are now a number of vaccines in clinical trials for cancer, which is considered a chronic disease, Janda says, so why not ones for obesity, diabetes, and drug abuse?

    “We know why we failed previously and that there are clear pathways in front of us,” adds Martin Bachmann, an immunologist formerly with Cytos Biotechnology. He says that poor antibody responses and lack of specificity—critical flaws for a vaccine—are problems that companies are now addressing by using full-length proteins, rather than peptides, and experimenting with viruslike particles that yield a higher and more consistent antibody response.

    Mite-y vaccine

    Vaccines were originally developed to combat microbial pathogens such as the smallpox virus and the tuberculosis bacterium; people are traditionally injected with live or dead copies of a pathogenic microbe, or with its molecular components—a viral surface protein, for example—to rally the immune system to produce antibodies or cells that specifically target the invader for destruction.

    Yet vaccines may be able to do more than prevent infections. Consider asthma, the target of one vaccine effort. Worldwide, more than 300 million people suffer from asthma, often sparked by a violent immune response to common environmental allergens. Current treatments include corticosteroids, which reduce inflammation but have side effects, and a procedure called desensitization in which asthma/allergy patients are given increasing doses of an allergen cocktail. But the success of desensitization varies from person to person and occasionally causes a life-threatening reaction: anaphylaxis.

    A team led by Bruno Pitard at the University of Nantes in France is now tackling asthma with a variation on the traditional vaccine. Pitard's strategy stems from the observation that 50% of Europeans with allergies harbor antibodies against the Der f 1 protein from Dermatophagoides farinae, one of the most common dust mites in the United States and Europe. But instead of immunizing with actual Der f 1 proteins from this mite, which can trigger an allergic response in people with asthma, Pitard and his colleagues are testing a vaccine composed of DNA coding for the protein, with the idea that it would train the immune system to tolerate it.

    Vaccine recipe.

    First produce a viruslike particle, then chemically link multiple copies of an antigen, such as nicotine. The result: a conjugate vaccine that triggers strong antibody production.


    When naked DNA is injected into the body, however, it is rapidly degraded before it can express the antigen it encodes. That problem has frustrated many developing naked DNA vaccines, so Pitard is now treating his Der f 1 DNA with so-called tetrafunctional block copolymers, which, as his team discovered in 2009, encourage gene delivery into the skeletal muscle, where the protein can then be manufactured. The team recently immunized mice using this modified vaccine, and those mice had a fivefold reduction in their asthmatic reaction, Pitard says. Lung tissue and bronchioles carried far fewer inflammatory cells and cytokines than in asthmatic mice vaccinated with a placebo. Despite that encouraging data, it will be at least 5 years before a clinical trial of the asthma vaccine begins, Pitard predicts.

    Most candidate vaccines for chronic diseases don't target microbial molecules but proteins made by the human body. Take the strategy behind the original Alzheimer's disease vaccine, which sought to activate the immune system against β amyloid. Because of the dangerous brain inflammation that followed, companies have largely turned to a so-called passive immunization, an approach in which they create antibodies targeting β amyloid outside the body, then inject them (Science, 17 August, p. 790). But several companies are still studying vaccines against different forms of β amyloid, which they hope will not produce the same side effects.

    The various obesity vaccines also go after natural human proteins. Somatostatin, a small peptide hormone produced in the hypothalamus, inhibits growth hormone and insulin-like growth factor, which increase metabolism. The interest in a somatostatin vaccine for humans began when Haffer was searching for another use for Braasch Biotech's vaccine Somatovac, which they found was a promising way to boost milk production in cows and lean meat production in pigs without using bovine growth hormone or antibiotics. He realized that Somatovac might also promote leanness in humans and therefore fight obesity.

    Haffer sent two different versions of the somatostatin vaccine to Jackson Laboratory in Bar Harbor, Maine, where researchers there tested them on mice that had previously bulked up from consuming a high-fat diet for 8 weeks. Neither vaccine made the already-plump rodents lose weight, but they gained 10% less weight than control rodents, even though all the animals ate the same quantity of high-fat food during the 6-week study, Haffer reported in July in the Journal of Animal Science and Biotechnology.

    The concept of creating vaccines for diseases like obesity isn't outlandish, but choosing the target is tricky, says George Jackson of the University of Texas Medical Branch in Galveston, a neuroscientist who is working on a next-generation vaccine for Alzheimer's disease. With Alzheimer's, he points out, you could potentially “target Mr. Hyde without harming Dr. Jekyll” because the culprit—a rogue form of β amyloid—appears to have no beneficial role. Obesity is different, he says: “Somatostatin is doing something bad but also something good. A vaccine could cause side effects by interfering with that normal function.” Immunizing against an endogenous hormone controlling appetite might cause anorexia or wasting away, for example.

    Haffer isn't the first to dream of an obesity vaccine. Janda and others have targeted the appetite-stimulating hormone ghrelin in their attempts to build an obesity vaccine. Back in 2006, Janda made headlines similar to those received by Haffer's work when he and colleagues reported that vaccinating adult male rats with a segment of ghrelin protein, or the full-length version, slowed weight gain and fat buildup in the body but didn't seem to affect appetite. Janda cautioned at the time that the study rats dined on a mundane, low-fat, low-energy chow. He couldn't predict from this study whether the vaccine would prevent diet-induced obesity—the kind that afflicts many people consuming a high-fat Western diet—or trigger weight loss in animals that were already obese.

    Mariana Monteiro, an endocrinologist at the University of Porto in Portugal, presented more evidence at The Endocrine Society's Annual Meeting in June 2011 that an antighrelin vaccine could reduce appetite-promoting brain chemicals in mice. She revealed that tethering ghrelin to a viral protein could trigger enough antighrelin antibodies in the rodents to reduce eating, increase energy use, and reduce levels of neuropeptide Y—a potent appetite stimulator. But there was no overall weight loss at the end of the study. Monteiro wrote in October 2011 in Expert Review of Vaccines that the underwhelming impact on long-term food intake and body weight “might be due to activation of compensatory mechanisms.”

    Janda and his team have also explored passive immunization: injecting antighrelin antibodies in mice. In a study published in February in Molecular Pharmaceutics, Janda's team showed that a cocktail of three monoclonal antibodies targeting ghrelin could curb appetite and increase energy use. While this isn't really a ghrelin vaccine because it bypasses the immune system, it similarly “protects” the mice from the hormone and dulls its role as an appetite stimulant.

    Even with expanding numbers of overweight and obese people worldwide, Janda's results so far haven't secured him National Institutes of Health funding to further develop a ghrelin vaccine. He's skeptical himself about tackling obesity this way. “I don't think there is one controlling molecule for metabolism,” he says. “It's not going to be a panacea for all obesity.”

    Bachmann suspects that trying to develop a vaccine for obesity is hopeless. “It's so complicated,” he says, “and people love to eat.” An obesity vaccine is fighting all the evolutionary safeguards that encourage an animal to eat and ward off starvation. He's also not convinced that mice are a reliable indicator of whether an obesity vaccine will work in humans, noting that “every animal has different feeding behavior.”

    Nullifying nicotine

    Bachmann remains more optimistic about a potential nicotine vaccine that could help people stop smoking, even though those efforts, too, have stumbled. A nicotine vaccine is subtly different from—and potentially safer than—those targeting obesity-related molecules or Alzheimer's disease protein. The strategy, as with other so-called addiction vaccines for heroin and cocaine, is to create enough antinicotine antibodies in the blood to diminish the amount of the compound that makes it to the brain, in theory making an individual cigarette less appealing. Nicotine isn't normally in the body, so there arguably should be less risk of side effects from inducing antibodies that block it.

    In the late 1990s, scientists at Nabi developed and began testing NicVAX, a traditional conjugate vaccine that tethered nicotine, which by itself is so small that it's invisible to the immune system, to a readily detected bacterial protein. Animal studies were promising: The vaccine stimulated the production of antibodies that bound much of the nicotine in the blood before it reached the brain, suppressing the pleasurable nicotine high.

    The initial clinical trials examining NicVAX's safety revealed no significant concerns, and by late 2007 Nabi announced that additional Phase II trials had allowed it to zero in on the most effective vaccine dose. The company also found that among the vaccinated smokers, the antibody response correlated closely with the ability to quit and remain abstinent. Late last year, however, the happy ending did not materialize. Nabi announced that its Phase III trial of NicVAX was a failure: There wasn't a significant difference between the percentage of quitters in the NicVAX group and the placebo group.

    Others are also finding an anti-smoking vaccine elusive. In 2008, Bachmann and his colleagues at Cytos tested their own nicotine vaccine in 341 smokers in a 6-month randomized, controlled Phase II clinical trial; 229 were given the vaccine while 112 received the placebo, administered monthly. After 2 months, the number of quitters in the vaccine group was significantly higher than the placebo group, 47% versus 35%.

    But after 6 months, the difference between the two groups was negligible. A closer look at the data offered some hope: The “high responders,” the people who produced the highest levels of antinicotine antibody in response to the vaccine, enjoyed the greatest success. Of the high responders, 57% had abstained from smoking after 6 months, compared with 31% of the placebo group. At 1 year, the numbers dropped to 41% and 21%, respectively, which Bachmann calls “statistically and clinically significant.” “Only one-third of the patients had a high antibody response,” he says. “If we could improve that by a factor of 3, then we might have a product.”

    Vaccine development is an expensive game, however, and Cytos ran out of money a year ago. Bachmann has since launched two companies, Areba and Saiba, which focus on vaccines for Parkinson's disease, malaria, and Alzheimer's disease. “I don't have the money to do smoking,” he says, though he is still a “great believer” in the nicotine vaccine.

    An expanding epidemic.

    A vaccine that could reduce weight gain would have a domino effect on other chronic conditions such as coronary heart disease, type 2 diabetes, and high blood pressure.


    Producing enough antibodies to bind to the 500 micrograms of nicotine in a cigarette before it crosses the blood-brain barrier in 6 to 10 seconds is a formidable hurdle. One radical strategy to meet that challenge, described on 27 June in Science Translational Medicine, is more akin to gene therapy than a vaccine. Janda and collaborator Ronald Crystal, a pulmonologist and genetic medicine expert at Weill Cornell Medical College in New York City, injected mice with a virus that travels to the liver, carrying the gene for a monoclonal antibody with a high affinity for nicotine. There, infected cells release antinicotine antibodies into the blood.

    “When you give nicotine to mice, they chill out like people,” Crystal says. Their blood pressure and heart rate drop by almost half within 25 minutes. Mice that received the team's “vaccine” were unaffected when later given nicotine, running around with no change in blood pressure or heart rate. When Crystal's team analyzed the animals' blood samples, they found that 83% of nicotine in the serum was bound to the antibodies made by the inserted gene, preventing it from reaching the brain and triggering the dopamine reward system. In the brain, nicotine concentrations were just 15% of that in untreated control animals.

    “It's a second-generation vaccine for addictive molecules. It's more elegant. It produces more antibody,” Crystal says, adding that the virus carrying the monoclonal antibody gene is currently being tested in another gene therapy clinical trial, so he's confident of its safety record.

    A nicotine vaccine interests Big Pharma, Janda notes, “because there's money in it.” Smoking causes about one in five deaths in the United States each year, is responsible for 90% of lung cancer in men and 80% in women, and boosts the risk of stroke and heart disease twofold to fourfold.

    Pharmaceutical companies may indeed see a big market for a nicotine vaccine, but they're not sure anyone can deliver a safe, effective product. “Novartis has made some contracts with biotech companies to develop antismoking vaccines,” says Rino Rappuoli, global head of vaccines research for Novartis Vaccines and Diagnostics in Siena, Italy, “but there has not been much progress. Big companies rely on biotechs to derisk the sector.” As the stumbling efforts to immunize people from Alzheimer's, obesity, and smoking attest, however, developing vaccines for chronic diseases remains a risky proposition.

    • * Bijal Trivedi is a freelance writer in Washington, D.C.

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