News this Week

Science  19 Feb 2010:
Vol. 327, Issue 5968, pp. 928
  1. Brazil

    Race for Cellulosic Fuels Spurs Brazilian Research Program

    1. Antonio Regalado

    CAMPINAS, BRAZIL—The ambition of plant biologist Marcos Buckeridge is echoed in the works he listens to during his commute to a new research laboratory here in Brazil's sugar-cane country. Right now, he's into American Prometheus, a biography of J. Robert Oppenheimer, father of the Manhattan Project; next, a history of the U.S. space program.

    Buckeridge is hoping to keep Brazil in another international technology race. He is the scientific director of Brazil's Bioethanol Science and Technology Center (CTBE), a $40 million facility inaugurated on 22 January. His task: to organize a world-class research program. “The Americans are spending more money,” says Buckeridge, “but if we succeed, we will be regarded like Pelé, and scientific discovery will be treated as an act of heroism in Brazil.” At stake is Brazil's position as the world's most efficient producer of ethanol.

    Brazil got its start running cars on ethanol during a 1970s oil-independence push. These days, nearly every new car sold in Brazil can run on it. The country's sugar-cane mills make ethanol for half of what it costs in the United States, where ethanol is made from corn. Exports have surpassed 3 billion liters per year.

    Raising cane.

    President Luiz Inácio Lula da Silva and plant biologist Marcos Buckeridge at the inauguration of Brazil's national Bioethanol Science and Technology Center last month.

    CREDIT: GUSTAVO TILIO/CTBE

    Keeping that lead won't be easy. Although Brazilian sugar cane is the most competitive ethanol feedstock today, the United States and Europe are investing heavily in next-generation approaches. In 2009, the U.S. Department of Energy alone budgeted more than $325 million for biofuel science and demonstration plants. Much of that effort is aimed at “cellulosic ethanol,” or how to obtain fermentable sugars cheaply from straw, wood chips, and other plant material normally considered waste (Science, 16 March 2007, p. 1488).

    CTBE represents Brazil's big bet to keep pace in cellulosic technology. Construction has started on a $12 million pilot plant, where scientists from across Brazil will study how to use enzymes to break down and access sugars that normally remain trapped in sugar-cane straw and processed stalks, known as bagasse. “Not investing would be a very big risk,” says Marco Aurélio Pinheiro Lima, a theoretical physicist who is CTBE's director. “Brazil would end up having to purchase technology in areas it has always led. The government is very aware of that.”

    Until now, Brazil's biofuel research has had a strongly practical bent. Industry agronomists developed new cane varieties, and steam-power experts taught sugar mills how to burn cane waste and make electricity. Engineers in Brazil also led the development and launch of flex-fuel vehicles that burn both ethanol and gasoline. Since 1975, the amount of ethanol squeezed from each acre of sugar cane has more than doubled.

    Given that track record, not everyone in Brazil is convinced by the new cellulosic push. “The view I defend is that the first-generation technology still has space to improve,” says José Goldemberg, a professor at the University of São Paulo and former education minister. Goldemberg thinks that ethanol production can be vastly increased by expanding sugar-cane agriculture and introducing genetically modified crops, all well before cellulosic ethanol reaches economic viability. And because many Brazilian mills already burn cane waste to make electricity (producing about 3% of the country's electricity), there's competition for cheap cellulose. Suani Teixeira Coelho, director of the Brazilian Reference Center on Biomass at the University of São Paulo, thinks the new national lab represents “a kind of megalomania. They are thinking if we don't dominate the technology, someone else will.”

    Buckeridge says it's critical that Brazil play a role in developing next-generation technology. He notes that about two-thirds of sugar cane's sugars remain trapped in straw and bagasse in forms that ethanol-producing yeast can't digest. Using conservative estimates, he calculates that cellulosic technology could increase per-acre ethanol production by 40%. “I don't think you're going to get that with the first-generation technology,” he says.

    CTBE grew out of a study commissioned by Brazil's Ministry of Science and Technology in 2005 that concluded that the country needed an internationally competitive national lab to coordinate its growing research efforts. Although precise figures are not available, public-sector funding for biofuel research has grown in Brazil by some 500% during the past decade and now totals about $90 million per year, says Carlos Henrique de Brito Cruz, scientific director of the State of São Paulo Research Foundation. “The main change in Brazil's strategy in bioethanol is making it much more science-based,” says Brito Cruz. That's a recognition that the competition comes from “countries that use a lot of science to improve their technology.”

    Brazil's government has been anxious about losing ground. In 2008, science minister Sérgio Rezende publicly complained when Monsanto paid $290 million to acquire two homegrown biotech start-ups, Alellyx and Canavialis, then developing new sugar-cane varieties. Rezende lamented the loss of two domestic technology “jewels” to “foreigners.” Yet Monsanto turned out to be only among the first in a wave of multinationals looking for footholds in Brazil. This month, Royal Dutch Shell agreed to a $12 billion joint venture with Brazil's largest ethanol producer, Cosan. As part of the deal, Shell contributed its stake in two cellulosic ethanol start-ups, indicating that it planned to apply the technology first in Brazil.

    “Everyone wants to play in Brazil because of the cheap sugar. The technology is going to come whether Brazil develops it or not,” says Carl E. Pray, an economist at Rutgers University, New Brunswick, who has been studying international aspects of biofuel R&D. Pray thinks Brazil stands to reap the benefits first no matter where cellulosic technology is developed: “Stuff that is developed in a lab in the U.S. is moving to Brazil that night by e-mail.”

    CREDIT: (SOURCE) THOMSON REUTERS, SCIENCE WATCH

    For Brazilian academics, the growing interest in sugar cane is a chance to forge new international relationships. Last year, Brazil's federal science agency issued a joint call for proposals to develop cellulosic ethanol with the European Union. For its part, CTBE signed a cooperation deal with the U.S. National Renewable Energy Laboratory. “We each work on our own feedstock but then trade notes,” says Pinheiro Lima.

    So far, CTBE's offices and laboratories are mostly empty. But equipment has begun arriving, and the center plans to have 170 scientific and technical staff by 2013. The laboratory will focus on some immediate problems, such as developing farm machinery that uses GPS to run along trails and avoids compacting soil. But cellulosic technology remains the top goal. Starting next year, the lab will carry out what it terms “mega-experiments” to test ideas from researchers across Brazil in the pilot plant's fermentation tanks and enzyme chambers. “For Brazil to have a role in this technology, we will have to work together,” says Pinheiro Lima.

  2. U.S. Congress

    Ehlers's Retirement Called 'Big Loss' for Science

    1. Jeffrey Mervis

    Vernon Ehlers, a staunch supporter of science and one of three physicists in the U.S. House of Representatives, is retiring after 17 years in Congress.

    His announcement last week, which came as Washington, D.C., grappled with a historic blizzard, was characteristic of the soft-spoken, self-effacing former college professor. The 76-year-old Republican from central Michigan has been a quiet but insistent force on the House science committee, working with both Democratic and Republican chairs on legislation to improve U.S. science and math education and bolster federal investments in research. His retirement at the end of the year will strip the science committee of arguably its two most influential members following a similar decision by its chair, Representative Bart Gordon (D–TN), not to seek reelection after 26 years in the House.

    “Mr. Science.”

    Ehlers hopes to stay involved in science policy.

    CREDIT: U.S. CONGRESS

    “It's a big, big loss,” says Sherwood Boehler, a former chair and a moderate Republican who retired in 2006. “He was Mr. Science in Congress, and he was my go-to guy whenever I had a question about research or science education.”

    Although Ehlers told Science that he felt “it was time to move on,” his retirement won't quench his lifelong passions. “I hope to stay involved,” Ehlers said. “I've spoken to some of the powers-that-be in Washington, and I think I can still play a role.” Ehlers said he couldn't talk yet about his new gig, noting only that “I won't be doing it for the money.” He also wants to become “an elder statesman” on behalf of continued federal support for research.

    Not one to toot his own horn, Ehlers nevertheless says he's concerned about the continued vitality of the science committee with his and Gordon's departure. “That was actually the biggest factor in my mind against retiring,” he explains, noting that he considered retiring 2 years ago but changed his mind. “I recognize the role I've played on the committee over the years. But there are still some good people there who care a lot about science.”

    David Goldston, a longtime aide to Boehlert and former committee staff director, describes Ehlers as “thoughtful and independent, … willing to work with anybody who takes these issues seriously.” Now head of government affairs for the Natural Resources Defense Council, Goldston says Ehlers “is the kind of member that Congress needs more than ever these days.”

  3. China

    Fear of MRI Scans Trips Up Brain Researchers

    1. Li Jiao*

    BEIJING—Neuroscientist Zang Yu-Feng and his colleagues at Beijing Normal University plan to use functional magnetic resonance imaging (fMRI) to probe differences in brain activity between healthy children and those with attention deficit hyperactivity disorder. Intending to enroll children in the study, university students last December handed out fliers at a primary school. But they came away empty-handed: Parents were worried that MRI scans might harm their children.

    Although MRI is widely embraced in China as a diagnostic tool, parents are reluctant to expose children to strong magnetic fields. Such unease is not the only impediment. “It's getting harder to do MRI studies because public distrust of doctors is increasing,” says Xie Sheng, a radiologist here at Peking University First Hospital. Reasons for distrust include heightened awareness of patients' rights and more debate in the media about the relative merits of different treatments, she says. The challenge of recruiting healthy children for studies has compelled Xie, for one, to resort to ill children—an approach that can backfire.

    MRI marks the spot.

    Tan Li-hai's group found that dyslexic Chinese children, compared with controls, had less activity in a brain region important for Chinese reading and writing.

    CREDIT: W. T. SIOK ET AL., PNAS 105, 14 (8 APRIL 2008) © NATIONAL ACADEMY OF SCIENCES, U.S.A.

    After 3 decades in the clinic, MRI is considered safer than x-ray scans and proton emission tomography, says physicist Yihong Yang, chief of the MRI physics section at the National Institute on Drug Abuse in Baltimore, Maryland. The main danger is for people with a pacemaker or other metal in their bodies. “Millions of people have been examined with MRI so far; thus it seems now very unlikely that there would be a side effect,” says Arno Villringer, director of cognitive neurology at the Max Planck Institute for Human Cognitive and Brain Sciences in Leipzig, Germany.

    In China, that reassurance cuts little ice with many parents—and some scientists. “I would not dare to allow my children to be tested by MRI,” says radiologist Han Hongbin of Peking University Third Hospital. “Nobody can ensure that there is no potential danger,” such as during nonroutine MRI scans that use extremely powerful magnetic fields, he says.

    In the face of such concerns, some researchers take shortcuts. For example, Xie recently submitted a report to Epilepsy Research on epilepsy in toddlers. Last month, however, the journal rejected her article because her control subjects were unhealthy. Xie acknowledges that's true: Most children she classified as controls had undergone MRI exams for other complaints. “It is too hard to recruit perfectly healthy children to take an MRI test,” Xie says.

    Some colleagues sympathize and suggest that exceptions to standard research practice should sometimes be allowed. Zang says that in Xie's case, children who are not afflicted with epilepsy and have no neurological complaints—but who may suffer from other ailments—are permissible controls. Not so, says Huang Ruiwang, a magnetic resonance physicist at Beijing Normal, who argues that it was correct to reject Xie's article.

    Recruitment goes more smoothly in the United States, where “many parents will allow their children to take the test,” says Damien Fair, a neuroscientist at Oregon Health and Science University in Portland. Even in China, some groups have had more success. Tan Li-hai, co-director of the State Key Laboratory of Brain and Cognitive Sciences at the University of Hong Kong, says he has never had trouble recruiting subjects for studies; his team recently identified brain regions crucial for reading and dyslexia in Chinese children.

    Tan's success heartens Zang, who believes his group can get its study back on track. They will resume their recruitment drive after the Lunar New Year festival ends this week—although Zang says that this time around they will work harder to better inform parents about their research aims.

    • * Li Jiao is a writer in Beijing.

  4. ScienceNOW.org

    From Science's Online Daily News Site

    New Challenge to 'Chronic Fatigue Virus' A theory linking chronic fatigue syndrome (CFS) to an infectious mouse virus known as XMRV has taken a second major hit. First proposed last October, the virus-CFS connection was quickly challenged by a British group. Now a second team of British virologists reports that, after examining tissue from 170 CFS patients, they have failed to find evidence of XMRV.

    CREDIT: CDC

    What Doesn't Kill Microbes Makes Them Stronger If you are taking antibiotics, your doctor will admonish you not to skip any pills and to continue the treatment even after you start to feel better. That's because failure to kill the bugs making you sick can cause some of them to become resistant to the antibiotics. Now, a new study explains how nonlethal antibiotic concentrations can lead to resistance. The drugs trigger the release of so-called reactive oxygen species inside bacteria, which in turn cause mutations in the bugs' DNA—including some that happen to cause resistance.

    Holy Surgical Side Effect People of many religious faiths share the belief that there is a reality that transcends their personal experience. Now, a study with brain cancer patients hints at brain regions that may regulate this aspect of spiritual thinking. The researchers found that some patients who had surgery to remove part of the parietal cortex became more prone to “self-transcendence.”

    First Gene Mutations Linked to Stuttering Researchers have pinpointed the first genetic mutations responsible for stuttering. The find links the condition, which afflicts about 5% of children and 1% of adults, to metabolic disorders and could lead to new treatments.

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

  5. Invasive Species

    Biologists Rush to Protect Great Lakes From Onslaught of Carp

    1. Erik Stokstad

    With Asian carp poised to invade Lake Michigan, wildlife managers are urgently trying to figure out how many of the voracious 1.5-meter-long fish have already slipped past electric fish barriers in a waterway near Chicago—and they are scrambling to shore up defenses. A new plan, released by federal agencies and other groups last week, aims to improve coordination among agencies dealing with the immediate threat and divvies up $78.5 million for control and research. Meanwhile, scientists and advocacy groups are pushing with renewed effort for what they say is the only long-term solution: severing the connection between the Great Lakes and the Mississippi River Basin, a proposal that doesn't sit well with the barge industry.

    Pressing onward.

    DNA tests indicate silver and bighead carp (left) have passed electric barriers.

    CREDITS (LEFT TO RIGHT): ASIAN CARP MANAGEMENT; (SOURCE) THE NATURE CONSERVANCY AND UNIVERSITY OF NOTRE DAME, USACE

    The two invasive species—bighead carp (Hypophthalmichthys nobilis) and silver carp (H. molitrix)—are native to China and were introduced for aquaculture in the southern United States in the 1970s. After escaping, the fast-growing, fecund fish moved up the Mississippi River and its tributaries. In some places, the carp have caused a 90% decline in crustacean zooplankton and are apparently outcompeting two native fish species, the gizzard shad and bigmouth buffalo. In addition, silver carp jump high out of the water when startled and have caused broken bones and concussions in boaters. Although eaten around the world, Asian carp have too many bones for the taste of most U.S. anglers.

    Worried about the threat to the $7 billion recreational fishing industry in the Great Lakes from this and other invasive fish, Congress authorized the U.S. Army Corps of Engineers in 1996 to build a prototype electric fish barrier within a key choke point—the Chicago Sanitary and Ship Canal (Science, 11 July 2003, p. 157). After testing started in 2002, a second, full-scale barrier was added to help repel any fish that try to swim upstream through it. From monitoring the canal and the Illinois rivers, wildlife managers believed that the invasion front was still 25 to 30 kilometers south of the barriers.

    But last year, they got a rude shock. David Lodge, an invasive species biologist at the University of Notre Dame in Indiana, began testing water samples for Asian carp DNA. Working with The Nature Conservancy, the team discovered DNA from silver and bighead carp several places above the barriers. Fish biologist Phil Moy of Wisconsin Sea Grant in Manitowoc believes the carp may have passed through the barriers a few years ago either during a power outage or when they were down for maintenance.

    Most alarming, in December, Lodge's team found bighead and silver carp DNA in the mouth of the Calumet River—suggesting that some fish could already be in Lake Michigan. “That's what really lit a fire under everybody's seat,” says Marc Gaden, legislative liaison of the Great Lakes Fishery Commission in Ann Arbor, Michigan. Soon, wildlife biologists netted a bighead and a silver carp where they found DNA.

    The most immediate eradication measures are admittedly a stopgap. Over the next few weeks, the U.S. Fish and Wildlife Service and partners in Illinois will put more than 20 staff in up to nine boats for electrofishing and netting the carp, to the tune of $2.6 million. It won't be easy. “They are very difficult fish to catch at low density,” cautions biologist Duane Chapman of the U.S. Geological Survey (USGS) in Columbia, Missouri. “The chances of getting all of them are close to nil.” Still, he says, the more fish kept out of the Great Lakes, the better the chance of preventing an established population.

    The strategic plan also includes $13 million for the corps to speed completion of a third electrical barrier, now expected by October. Another $13.2 million would accelerate construction of physical barriers on the Des Plaines River and a canal to prevent fish from moving through with floodwaters. Additional funds would go toward developing selective “bubble” barriers to keep fish from spawning areas in the Chicago-area waterways or, if necessary, in the Great Lakes. There's also $1.5 million for USGS to work on formulating fish poison that targets only Asian carp and $1 million to study pheromones that might help trap or deter carp.

    The surest way to prevent carp from getting established, scientists say, is to achieve “ecological separation” by permanently closing the locks in Chicago and creating physical barriers to water flow in the other entry points to Lake Michigan. That might pose problems for the 50,000 or so recreational and commercial boats that pass through the Chicago River Lock each year. One option, say advocates, is to lift the boats over, but the American Waterways Operators opposes any substantial changes. In December, Michigan's attorney general sued the state of Illinois, demanding that the canal locks be closed, but the U.S. Supreme Court declined to hear the case.

    Lodge and others says that an investment in separating the waterways would pay off by also preventing other invasive species, such as the northern snakehead fish, from reaching the Great Lakes—and reducing the odds that any of the more than 180 invaders in the lakes will travel inland via rivers. “It's far more expensive to always be reacting” to invasions, he says.

    As part of the new plan, the Army Corps has moved up the deadline for its comprehensive study of how to prevent the movement of invasive species between the Great Lakes and the Mississippi River Basin to 2012. That's not fast enough for Gaden and others. “We don't have the time,” he says. There will be quicker action, according the strategic plan: By 30 April, the corps could begin modifying Chicago River Lock operations—opening it for only a few days a week, for example—to reduce the chance of carp getting through.

  6. U.S. Immigration Policy

    Prominent Iranian Scientist Blocked From Attending Physics Meeting

    1. Yudhijit Bhattacharjee

    Iranian physicist Farhad Ardalan has spent enough time in the United States to regard it as his second home. But a case of apparent mistaken identity may prevent him from ever visiting his adopted country again.

    Last fall, Ardalan was named a fellow of the American Physical Society, in part because of his efforts to connect Iran to the global scientific community and strengthen bonds between Iran and the United States. The new class of fellows will be honored at the society's meeting next month in Portland, Oregon. But U.S. consular officials have derailed Ardalan's application for a visa after telling him that U.S. government records show he was arrested in the United States in 1983 for an unspecified offense. They also say that he may have been involved in deportation proceedings 20 years earlier.

    Ardalan denies both charges, and his U.S. colleagues say that the State Department is making a big mistake. “He is precisely the kind of person who should be welcomed to the U.S.,” says Stanford University physicist Herman Winick about Ardalan, a string theorist at the Institute for the Study of Fundamental Sciences in Tehran.

    Visa problems.

    Farhad Ardalan suspects a “doppelgänger” has tainted his application.

    CREDIT: COURTESY OF FARHAD ARDALAN

    Ardalan first came to the United States in 1958 and attended Columbia University, where he received his bachelor's and master's degrees. After earning his Ph.D. in 1970, he returned to Iran to teach at Sharif University, where he helped create the first Iranian doctoral program in physics.

    Ardalan spent sabbatical years at Yale and Stony Brook universities in 1974 and 1977 and made a short visit to the United States in 1986. He claims that, like most Iranians, he wasn't allowed to leave the country for several years after the 1979 Iranian Revolution. “I simply could not have been in the U.S. in 1983,” he says about the government's charge, which he first learned about when he appeared for his visa interview on 29 January at the U.S. Embassy in Bern, Switzerland. (Iranians must go abroad for a U.S. visa.)

    When Ardalan disputed the charge, he says, the official told him that his name and fingerprints matched the record of the arrest and that he would have to come back for another appointment to give officials time to look into the case. “I said, ‘Forget it.’ And I left,” says Ardalan.

    On 2 February, an e-mail from the U.S. Embassy leveled a new charge. “A check of U.S. records appears to suggest that you were involved in deportation proceedings before the New York office of the Immigration and Naturalization Service on July 5, 1962. Please confirm or dispute this information,” the e-mail said.

    “I don't know what they are talking about,” says Ardalan. He says neither of these two charges were raised in 1993 when he and his wife received permanent residency in the United States. For the next decade, Ardalan spent several months every year as a visiting scientist at the University of Cincinnati in Ohio, working with his friend Freydoon Mansouri. Ardalan moved back to Iran after Mansouri died in 2003.

    Ardalan guesses that the problem is a doppelgänger. “There was a person with the same name who was a leader of the Kurdish guerrilla movement; as a result, for years I was routinely stopped and interrogated at the Tehran airport,” Ardalan says. It took a meeting with the head of airport security to clear his name. Ardalan says he deserves an apology for how he has been treated, and he refuses to go back to the embassy or reapply for a visa.

    State Department officials did not return calls for comment. The department has been criticized for botching visa applications of prominent scientists, including Goverdhan Mehta, an Indian chemist whose visa application was denied in 2006 (Science, 17 February 2006, p. 933).

    “We hope the issue can be resolved and Ardalan can come to the March meeting,” says John Clark, a physicist at Washington University in St. Louis, Missouri, and former chair of APS's Forum on International Physics. The meeting runs from 15 to 19 March.

  7. ScienceInsider

    From the Science Policy Blog

    The United Nations has formed a joint task force of experts from Haiti and around the world to provide advice on recovering from last month's disaster. The team hopes to generate a preliminary forecast of seismic activity and provide day-to-day advice to assist relief and recovery efforts.

    The new chief of Europe's top science policy office says she's “passionate” about using research and innovation to spur economic development and push governments to invest 3% of their gross domestic product on science. Ireland's Máire Geoghegan-Quinn thinks that not being a scientist may actually help her to “break down the barriers” to gaining greater public support.

    First Lady Michelle Obama has launched a major initiative on childhood obesity that features a new nonprofit foundation. Let's Move embraces better school lunches, more exercise, and more accessible healthy food, including financial incentives to bring farmers' markets and full-service groceries to urban areas.

    A long-running battle among farmers, conservation groups, and U.K. science advisers took a new turn when a team from the U.K. Medical Research Council reported that systematic culling of badgers does reduce outbreaks of bovine tuberculosis in British cattle but not enough to justify the cost of the cull. The finding likely won't end the controversy.

    Foreigners living in one of the world's most polluted cities now have more information about the quality of the air in Beijing. The U.S. Embassy, which has been using Twitter to publish average hourly readings of fine particulate matter, has also begun tweeting hourly data on ground-level ozone, the prime component of smog. But local residents will have to use a proxy server to access the data because Twitter is blocked in China.

    For the full postings and more, go to blogs.sciencemag.org/scienceinsider.

  8. Newsmaker Interview

    Embattled U.K. Scientist Defends Track Record of Climate Center

    1. Eli Kintisch

    Phil Jones is at the center of a swirling controversy over e-mails stolen or leaked from the Climatic Research Unit (CRU) at the University of East Anglia in the United Kingdom, which he has directed since 2004. In the 3 months since those messages came to light, Jones has been battered by criticism that the e-mails reveal a failure to share climate data publicly and an effort to prevent certain papers from being cited in international climate change reports. He's stepped down temporarily from his job to allow for an independent inquiry, and he's been treated for depression.

    But Jones hasn't walked away from the battlefield. “I've got no agenda here. I'm not a politician. I'm just a scientist,” he told Science during an interview last week from the University of East Anglia. Jones declined to talk about allegations concerning the hacked e-mails, citing the ongoing investigation. But he forcefully defended the quality of the center's efforts to create a global temperature database, which points to an average 0.1°C warming of Earth's land areas per decade since 1900. That work earned him a 2002 medal from the European Geosciences Union, among other acclaim.

    Here are some highlights from the interview. An extended version of this interview can be found here.

    Q:If the CRU data set were set aside, are there other data that corroborate your findings about rising temperatures?

    P.J.:There's the two other data sets produced in the U.S. [at NASA and the National Oceanic and Atmospheric Administration]. But there's also a lot of other evidence showing that the world's warming, by just looking outside and seeing glaciers retreating, the reduction of sea ice … overall, the reduction of snow areas in the Northern Hemisphere, the earlier [annual] breakup of sea ice and some land ice, and river ice around the world, and the fact that spring seems to be coming earlier in many parts of the world.

    Q:Critics say that your producing the same trends as the NASA and NOAA data sets is insignificant given that you start with the same raw data.

    CREDIT: UEA

    P.J.:There are differences. The two American sets use a larger number of [temperature] stations than we do. They both use about 7200 stations, and we use about 5000 stations. But we look at that data in different ways and have different techniques for deciding whether the stations are used or not.

    Q:One of the real challenges is going from the available raw data to the final temperature sets that you release. Do you feel that you have released enough information that someone could repeat that exercise?

    P.J.:Yes, I feel they have. [Our papers] have been peer-reviewed; we've been doing this work for almost 30 years now. [NOAA] has something called the Global Historical Climatology Network, and people can download the station data—it's essentially the same data, it may not be exactly the same—they could go and take that data, make their own choices about what stations to use, … they could reproduce their own gridded temperature data. A lot of the people at the moment criticize what we do but [are not doing] anything constructive and new.

    Q:A sticking point with some of your critics has been how much of the data isn't available.

    P.J.:We've been putting up more of the data online on the U.K. Met Office site [covering] 80% of the stations we use. You can download the data and you can download the program we use to produce the data sets.

    Q:One concern of your critics is whether there are adequate procedures in place to assure the quality of this data.

    P.J.:That's the sort of work we've done in the past and published in the papers.

    Q:You've emphasized that you have a small staff. Would more people checking these data be a useful thing?

    P.J.:It could be useful, but then we've got to bring them up to speed in terms of what we're looking for. … The national meteorological services [which provide the raw numbers] are doing quality control on this data before it even reaches us.

    Q:When during your career has pressure from outsiders to criticize or, as you would put it, “distort” your work become significant?

    P.J.:In 2007, [as] the blog sites started then. I had responded to some of these people in years earlier but had given up. … I just didn't have the time to respond. They didn't seem to want to understand.

    Q:One of the skeptics who wanted station data was Warwick Hughes. What did you mean when you wrote in an e-mail to him that “even if WMO [World Meteorological Organization] agrees, I will still not pass on the data. We have 25 or so years invested in the work.”

    P.J.:I'd rather not go there. It was an e-mail written in haste.

    Q:When did the pressure become severe?

    P.J.:In July 2009, we received 60 Freedom of Information requests in a few days—each request was for five countries' worth of data. We probably should've responded to these requests in a different way. We stand by the science that we were doing. Maybe we need to be more proactive and open about releasing data. But the 60 requests were just too much to deal with at that one time.

    Q:Do you have any regrets about how you handled the chapter you've co-authored in the 2007 IPCC report?

    P.J.:No regrets, but I don't really want to go talking about IPCC. I stand by that chapter.

    Q:Why are you speaking out now?

    P.J.:It just seems like the right time. It was too difficult back in November and December.

  9. Psychiatry

    Behavioral Addictions Debut in Proposed DSM-V

    1. Constance Holden

    In psychiatry, the only disorders that have been considered addictions are those involving alcohol or other drugs. Now, proposed revisions for the American Psychiatric Association's (APA's) Diagnostic and Statistical Manual of Mental Disorders (DSM) include for the first time “behavioral addictions”—a change some say is long overdue and others say is still premature (Science, 12 February, p. 770).

    So far, only one behavior has made the cut: gambling, which under the new proposal would join substance-use disorders as a full-fledged addiction. DSM has recognized pathological gambling for decades, but it has been consigned to a grab bag of “impulse control disorders not otherwise specified” along with kleptomania, hair-pulling, and fire-setting. Many scientists have long believed that compulsive gamblers closely resemble alcoholics, not only from the outside—destroying jobs, finances, and relationships in pursuit of their obsession—but, increasingly, on the inside as well. Brain imaging and neurochemical tests have made a “pretty strong case that [gambling] activates the reward system in much the same way that a drug does,” says psychiatrist Charles O'Brien of the University of Pennsylvania and chair of the addictions work group for DSM-V. Gamblers report craving and highs in response to their stimulus of choice; gambling also runs along with other addictions in the same families.

    Hooked.

    Brains of pathological gamblers watching a gambling video resemble those of cocaine addicts watching a cocaine video, with relatively less activation in regions implicated in judgment and motivation. Differences may reflect the toxic effects of cocaine exposure.

    CREDIT: YALE

    Psychologist Gerhard Meyer of the University of Bremen in Germany says he's been arguing since 1982 that pathological gambling should be classified as a behavioral addiction. Research by his group has shown that problem casino gamblers show increases in heart rate and salivary stress hormones as well as blood levels of norepinephrine compared with non-problem gamblers. The former also show increases in dopamine, the key player in the brain's “reward circuit.” Marc Potenza, a psychiatrist and gambling researcher at Yale University, says his group's brain-imaging studies show that when exposed to gambling videos, problem gamblers' brains show “important similarities” to changes in the brains of cocaine addicts when viewing a video about cocaine.

    Other behaviors may eventually follow gambling into DSM as addictions, as more is revealed about their neurobiology and genetics. The top contender at present is “Internet addiction,” which now has its foot in the DSM door; it will be listed in the appendix, a catch-all category for disorders that don't meet criteria for a full-fledged diagnosis. Some researchers have argued that people whose Internet use seems to be out of control show many hallmarks of addiction such as tolerance and withdrawal. But there is still no consensus on what constitutes so-called Internet addiction. Some argue that it is not the computer that's the issue but the content—mainly sex, gambling, and games—and that people hooked on the Internet suffer primarily from afflictions such as depression, personality disorders, and substance addictions.

    Some researchers say a case could be made for classifying some eating disorders, bulimia in particular, as addictions. Family studies show that bulimia clusters with alcoholism and drug abuse. “Binge eating disorder,” pulled out of the DSM-IV appendix and now proposed as a diagnosis in the eating disorders category, similarly has much in common with binge drinking. Columbia University physician Timothy Walsh, chair of the eating disorders work group, says he suspects “we'll discover underlying abnormalities in brain pathways” shared by addictions and some eating disorders. But as yet, diagnoses in his field are “still really descriptive” as opposed to biology-based.

    “Sex addiction” has received a lot of press lately, but O'Brien says his work group found “no scientific evidence” that sex qualifies. APA psychiatrist Darrel Regier, co-chair of the DSM task force, says “it's not clear that reward circuitry is operative in the same way as in addictive areas.” Nonetheless, a near equivalent may make it into the sexual disorders section of DSM: That work group is proposing a controversial new diagnosis of “hypersexual disorder.”

    The DSM teams have also tussled with the often-blurry line between addictions and compulsions. “I used to think [addictions] overlapped with OCD [obsessive-compulsive disorder],” says O'Brien. But new data from both brain-imaging and treatment studies suggest “more dissimilarities than similarities.”

    In another major change, O'Brien's group recommends dropping categories of “abuse” and “dependence” and labeling all problems major and minor as substance “use disorders” (or “disordered gambling”). Since the late 1980s, says O'Brien, “numerous large population studies” have shown there's no “breakpoint” where “abuse” becomes something more serious. He also says the term “dependence” only implies physiological dependence, which is not the same as the psychological obsession of addiction.

    Some longtime addiction researchers, such as psychiatrist Victor Hesselbrock of the University of Connecticut, Farmington, have qualms about the direction DSM is moving. Hesselbrock believes behavioral addictions are dicey territory and prefers to limit the term “addiction” to substances, which are “pathogens we can identify.” He also objects to fusing all drinking problems into “alcohol use disorder.” Hesselbrock says he and others think there are proven subcategories of alcoholism that would aid both in treatment and discovering causes. “When you do a one-size-fits-all type of classification system,” he says, “that will fit a lot of people but not so well.”

  10. Public Health

    Brawling Over Mammography

    1. Eliot Marshall

    A scientific study of the benefits and harms of screening women in their 40s got buried by the politics of health-care reform.

    The closer you look.

    Experts are debating the false positives in mammograms of younger women.

    CREDIT: JOE SONGER/BIRMINGHAM NEWS/LANDOV

    The Obama Administration is a self-described champion of science. But it was put on the spot last fall when it received a scientific report that questioned the value of screening women routinely for breast cancer before age 50. The timing was bad, coming just as Democrats were trying to push health reform through Congress. To opponents of the legislation, the report smacked of “medical rationing” by bureaucrats, the kind they claimed to see in the bills. It became a huge distraction, and in the end the Administration quietly distanced itself from the findings.

    The flap continued, loud and angry, for days. Experts and nonexperts lobbed critiques and rebuttals, at times questioning one another's motives. Authors of the report rejected the “rationing” charge, saying they never took cost into account. The nonprofit American Cancer Society, which had endorsed early breast cancer screening (at age 40), announced it wasn't going to change its recommendation. But a leader of the American College of Radiology, Daniel Kopans of Massachusetts General Hospital in Boston, was less restrained. He circulated a critique saying that the sponsor of the new report—the U.S. Preventive Services Task Force (USPSTF)—“does not think it is worth saving women in their 40s; … it thinks that women should be allowed to die from their breast cancers.”

    Secretary of Health and Human Services (HHS) Kathleen Sebelius weighed in on 18 November. Her agency is the official home of USPSTF, but she didn't defend its report. Instead, she ran for cover. She noted that USPSTF members are independent—not HHS staff—and were appointed in this case by George W. Bush. On CBS News, Sebelius advised women to “do what you've always done; … talk to your doctor.” Asked if she was “refuting” the task force, Sebelius said no, but added, “it is one panel of scientists and health officials who have waded into an area where the recommendations have gone back and forth for years.”

    Researchers who had worked on the USPSTF guidelines were disappointed that their analysis was being dismissed out of hand. “Politics got in the way of the science and the best public health practice,” says Jeanne Mandelblatt, an M.D.-epidemiologist at Georgetown University in Washington, D.C., and first author of an analysis for USPSTF by six groups that compared models to find the best screening strategy. “It was very unfortunate,” adds Heidi Nelson, an M.D.-epidemiologist at the Oregon Health & Science University in Portland, who led a separate team that gathered evidence for USPSTF.

    Karla Kerlikowske, a breast cancer researcher at the University of California, San Francisco, was “amazed” that “people were reacting in 1 day” to studies that took her a long time to read. “I am a big believer in science and evidence. … I thought people would really embrace the new science and say, ‘Wow, this is really good.’” One lesson she learned is that it's hard to take away something that has been promoted in the past—and mammography at 40 has been widely promoted. Second, Kerlikowske says, “people just didn't like the answer—that's what it came down to, unfortunately.”

    Fury over the 40s

    The argument over mammography was in many ways an echo of clashes over the same issues in 1996 and 2002, when USPSTF, an independent group whose advice is intended for primary care doctors and patients, issued its previous statements (Science, 21 February 1997, p. 1056; 1 March 2002, p. 1624). Indeed, many of the same protagonists came back to champion the same arguments. There was a difference, though: The 2002 USPSTF panel said that screening should begin at age 40; 7 years later, USPSTF said age 50 is when women with no known risk factors for breast cancer should begin screening.

    Asked how the data changed in 2009, USPSTF task force co-chair Diana Petitti, an M.D.-biostatistician at Arizona State University, Tempe, said, “No change.” She added: “The evidence has pretty much been the same all along; it's the packaging and the policy that goes with that packaging, and people's perceptions, … which seem to continually cause the controversy.”

    The task force did alter the packaging: It took a closer look than did the earlier report at the potential “harms” of mammography. These include downsides such as false positive x-ray results, extra doctor visits, biopsies, surgery, and the anxiety that goes with a result that indicates a possibility of cancer.

    Many clinical trials have indicated that screening with mammography benefits women over 50, mainly because they have a fast-rising risk of developing breast cancer. Abnormalities picked up by x-rays are more likely to be dangerous; treating them as cancer is more likely to save lives, and the “price” in false alarms seems worth paying. The panel concluded, however, that for women in their 40s, the benefits of routine screening by mammography don't outweigh the harms.

    CREDIT: SAMUEL ASHFIELD/GETTY IMAGES (DATA SOURCE) USPSTF

    When to begin screening is complex. No one proposes that teenagers be screened, for example. Young women aren't good candidates because their tissue may be more opaque to x-rays and because abnormalities, if found, are not likely to be life-threatening (Science, 9 September 2005, p. 1664).

    Common sense and individual experience—even a doctor's experience of treating cancer—isn't a guide, either. So says biostatistician Donald Berry of the M. D. Anderson Cancer Center in Houston, Texas. His warning applies especially to media reports like those aired last fall featuring young women who said that a mammogram had saved their life. Such testimony is powerful but not relevant, Berry says. “We are all duped by observations,” Berry said in an e-mail, “and much of the medical community buys into screening. Some (exemplified by Dan Kopans) have their professional reputations on the line.”

    The paradox, explains epidemiologist Steven Goodman of Johns Hopkins University in Baltimore, Maryland, is that “every woman who has been diagnosed through mammography feels that she benefited, but we know that even without the screening her cancer would have had a very high chance of successful treatment.” That is particularly true of a subcategory of small breast tumors known as ductal carcinoma in situ (DCIS), says Kerlikowske. Detection of DCIS has skyrocketed with mammography; incidence has increased 270% since 1987. Although nearly 100% of women survive DCIS, it's treated as cancer, often with surgery and chemotherapy, because it's not well understood, and—who knows?—it might be dangerous. The diagnosis of cancers that won't progress, known as “overdiagnosis,” is a “diabolical phenomenon,” according to Goodman, because it can be seen only “through the prism of a population view.”

    Parallels.

    Karla Kerlikowske is developing markers to distinguish risky from benign DCIS tumors; since the 1980s, detection of DCIS exploded with the rise of mammography.

    CREDIT: KARLA KERLIKOWSKE; (DATA SOURCE) AHRQ PUBLICATION, SEPTEMBER 2009

    The best guide to the benefits of screening, statisticians say, is to look at deaths among women who sign up for screening in trials and compare this with deaths among those who don't sign up. Nelson, who pulled together the data for the 2009 USPSTF review, conducted a meta-analysis combining the eight best randomized clinical trials since 1986. This review includes information not in the 2002 USPSTF study from older Swedish trials and from a new trial designed to look at women in their 40s, a U.K. study completed in 2006 known as the “Age” trial. (The Age study found a small benefit—breast cancer deaths were down 17% in the screening group—but it wasn't significant.) Women in the screening group had about 15% less likelihood of dying from breast cancer. Nelson's group calculated that this corresponds to prevent one death from breast cancer for every 1904 women screened in their 40s. By the same index, screening 50-year-olds prevents one death per 1339 women screened—a ratio the panel accepted.

    That small benefit is no surprise to Peter Gøtzsche, an epidemiologist who heads the Nordic Cochrane Center in Copenhagen, Denmark. Gøtzsche and Ole Olsen co-authored analyses a decade ago that dismissed mammography-screening programs at any age as having no benefit for healthy women. Organized mammography is hyped, Gøtzsche has said—a “medical scandal” that has “seduced” thousands. Even Gøtzsche, however, recently adjusted his reading of mortality data. A 2009 review he co-authored acknowledges that trials have detected a slight decline—about 15%—in deaths among women of all ages screened by mammography. But the review finds this is negated by false alarms and unneeded medical procedures.

    At the opposite pole is Kopans. He sees a scandal, too, but for him it's a conspiracy to obscure the good news that mammography works. Kopans has basic objections to the way that USPSTF and others slice the data. He claims that the 2009 USPSTF analysis used “the lowest possible” number from trial data to represent the average benefit of mammography for women in their 40s. He insists that experts should have cited a range of results from the best trials—from 15% to 44%. Or, he suggests, why not use the 44% benefit from the “Gothenburg” trial or the 35% benefit from the “Malmö” trial, both in Sweden. That's what he would do, and he credits mammography with reducing breast cancer deaths in the United States “by at least 30%” over 2 decades. And he insists that there is “no scientific support” for drawing a line at age 50. “The body doesn't know it's 50,” he says. Nelson has a terse response: “Fishing around to find an answer you like is inappropriate.”

    The dark side

    Few dispute the USPSTF panel's estimate of the benefits of screening, but its reading of harms is more controversial. For the first time in 2009, USPSTF produced a detailed list of negative outcomes. The new data are from the U.S. Breast Cancer Surveillance Consortium, a collaboration of U.S. community groups: For every 1000 women screened in their 40s, the review found 97.8 false-positive mammograms per round of screening (up to 10 times a decade), 84.3 call-back doctor visits, and 9.3 biopsies. (Exposure to radiation isn't flagged as a major concern.) Expressed another way, for every case of invasive cancer detected, 556 women have mammograms and five have biopsies.

    Churning.

    For every 1000 women in their 40s screened with mammography, about 100 initially get a false positive result.

    CREDIT: (DATA SOURCE) H. NELSON ET AL., BREAST CANCER SURVEILLANCE CONSORTIUM

    The false positives, the panel said, produce untold anxiety in addition to needless follow-up procedures. The report's attention to anxiety prompted snickers. In testimony for a House of Representatives panel in December, Petitti said, “The mention of anxiety and psychological distress as a harm of a false-positive test has … been ridiculed.” She added later that, “People are saying it's something we should ignore; I guess they've never been through a false-positive mammogram.”

    Goodman, who followed the debate closely, was also troubled by the gibes at the “harms” tally. He says he keeps a file of “cartoons that parody the reasoning of the task force, … really terrible stuff.” He thinks USPSTF was right; indeed, he urged the panel to be specific in a critique of its 2002 report. USPSTF authors, he wrote back then, were too “oblique” in adding up costs, and he called for hard data on the number of lumpectomies and mastectomies that follow false alarms.

    Goodman thinks the adverse effects are still soft-pedaled in the 2009 report. He says that he's “totally shocked” that “the word ‘mastectomy’ doesn't appear” in the list of potential harms. The USPSTF evidence team considered getting into unnecessary surgery, according to Nelson, but she says a co-author at the Oregon Health & Science University, oncologist Arpana Naik, recommended against it. The reason, Nelson says: Naik argued that women opt for a mastectomy out of fear even when test results don't indicate it's needed, and Naik “talks people out of mastectomies every day.” The team felt that the high surgery rate would reflect U.S. cultural norms, not medical norms.

    Mangled message

    The 2009 review aimed for a “nuanced” view of the risks and benefits of screening, Petitti says, that would predict what might happen under different screening strategies. For this, USPSTF turned to “the best modelers from the top research institutions,” says Mandelblatt. A group led by Berry, called the Cancer Intervention and Surveillance Modeling Network, drew on experience to estimate how different screening frequencies and starting points would affect the number of x-ray exams, deaths avoided, and false positives. The models plugged gaps in the trials. Among other things, Berry says, they confirmed the sketchy data on women in their 40s and “gave confidence” that screening recommendations would be solid—particularly that having a mammogram every second year was fine for women over 50. They also confirmed that new treatments have not made older trial data obsolete.

    The models led USPSTF to endorse the most efficient plan: Begin screening at age 50, screen every other year, and continue at least to age 74. Petitti later acknowledged that the technical language used in the message made it sound more negative than intended. When the furor erupted, USPSTF added a red-ink correction on the HHS Web site, making it clear that experts did not want women to avoid mammography and that women should “consult your doctor.” She concedes, “We communicated what we really meant poorly.”

    Goodman agrees. USPSTF's presentation of findings was stiff and failed to consider how to communicate risks to a lay public. The task force, Goodman says, “was not prepared for what ensued” when it fell into the “tinderbox” of the congressional debate on health care.

    Despite the intensity of the public disagreement that followed the release of the USPSTF recommendations, it's clear that people in all camps agree on at least one point: Research is needed to understand the biology of early-stage breast cancer better. Kerlikowske and others conclude that even the best analysis may not help the public understand risks if the disease is scary and the underlying biology is confused.

    A better understanding of DCIS and other early changes in breast tissue might make it possible to differentiate risk better and earlier. It might even help reduce the number of explosive policy brawls on mammography.

  11. China

    Leprosy's Last Stand—or Early Days of a War of Attrition?

    1. Richard Stone

    China thought it had licked leprosy 10 years ago, but the disease is stubbornly hanging on in poor, rural areas of three southwestern provinces, Guizhou, Sichuan, and Yunnan.

    JIANGYAN, CHINA—Shunned by his home village, You Yu-Gan has lived in a moatringed compound here in eastern China's Jiangsu Province for 40 years. In 1970, the farmer was diagnosed with leprosy and bundled off to Jiangyan Leprosarium. Treatment with the antibiotic dapsone tamed his infection, but his hands and feet were irrevocably disfigured and You, like many leprosy victims, languished in quarantine until a drug cocktail in the 1980s brought a long-elusive cure. Free to leave the leprosarium, You opted to stay. The other 118 residents are “like family,” explains You, 65, who earns a small income by helping in the clinic. Besides, he confesses, “I have nowhere else to go.”

    Some 20,000 disabled people still reside in 617 leprosaria or leprosy villages across China. After decades of neglect, the central government has launched a campaign to renovate decaying leprosy facilities. The overhaul is one prong of a reinvigorated strategy against an age-old malady that China nearly vanquished a decade ago but which persists mainly in remote parts of the southwest. To researchers' consternation, the number of new leprosy cases reported each year in China has held steady since the late 1990s. A fresh worry here is a possible uptick in resistance to rifampicin, the big gun in multidrug therapy.

    Four years ago, conferees at a World Health Organization (WHO) forum concluded that leprosy was “on the verge of defeat.” But the recalcitrant foe has not surrendered. “The transmission of leprosy is not totally interrupted yet,” says Denis Daumerie, WHO's project manager for neglected tropical diseases. “Based on our current tools and knowledge, it is impossible to eradicate the disease,” adds Wang Baoxi, director of the Chinese Center for Disease Control and Prevention's National Center for Leprosy Control (NCLC) in Nanjing.

    Nations have made great strides in bringing the disease to heel. Since a cocktail of rifampicin, dapsone, and clofazimine became standard treatment 30 years ago, the global disease burden has declined from 5.2 million cases in 1985 to just over 213,000 last year. Leprosy continues to bedevil a few countries—for example, more than half of new cases in 2009 occurred in India. But by WHO's definition, the disease was eliminated as a public health threat a decade ago when prevalence fell under one case per 10,000 people worldwide.

    Chinese officials have set a more ambitious target: They define elimination as a prevalence of less than one case per 100,000 people at the county level. A nationwide epidemiological survey in 1957 netted 300,000 cases, and by the early '70s, an army of village health workers called “barefoot doctors” was helping professionals ferret out patients and steer them to leprosaria. Prevalence fell from a peak of 23.5 cases per 100,000 people in 1966 to 0.5 cases per 100,000 in 2009, with the disease “eliminated” in 92% of China's 1464 counties—“a great achievement,” says Zhang Guocheng, president of the China Leprosy Association.

    Holding on.

    NCLC's Yan Liangbin and a Jiangyan patient he recently operated on. Leprosy is still a scourge in southwest China.

    CREDITS (TOP TO BOTTOM): R. STONE/SCIENCE; (SOURCE): NCLC

    But the endgame is shaping up as a long march. Early infections of Mycobacterium leprae easily evade detection; it can take up to 20 years before symptoms from the slowly multiplying pathogen show. New cases in China have hovered at about 1600 a year for the past decade, with most occurring in poor, rural areas of three southwestern provinces, Guizhou, Sichuan, and Yunnan (see map). Elsewhere in China, the majority of cases last year was among the 180 million workers who migrated to the industrialized east and south in search of jobs. “Leprosy detection in this floating population is a severe challenge,” Zhang says. An added complication is that in rural China, leprosy remains a social stigma. For that reason, Wang says, “many poor people refuse to be diagnosed.”

    Rifampicin resistance may pose a new threat. Whereas the other drugs in the cocktail hobble M. leprae, rifampicin slays it. Rifampicin-resistant strains emerged in the 1980s but may now be gaining traction in China. “We're seeing increasing numbers of cases with rifampicin resistance,” says Chen Xiangsheng, a senior epidemiologist at NCLC. The center is now setting up a national surveillance system for monitoring resistant strains.

    In the meantime, China is striving to make amends to the pariahs who have spent most of their adult lives in ramshackle wards. In December, Jiangyan Leprosarium completed a renovation of its 40-year-old facilities that included installing indoor plumbing, solar water heaters, and cable TV. The government is spending $32 million to refurbish leprosaria; after the leprosy victims die, officials say, the facilities will be used as hospices for AIDS patients or retreats for treating drug addicts.

    Leprosy victims are relishing the creature comforts. “It's much better here now,” says Gu Jin Fa, who at 54 years old is the youngest resident of Jiangyan Leprosarium. He smiles at NCLC's Yan Liangbin, who performed surgery on his feet a couple of years ago, enabling him to walk again after years in a wheelchair. Gu's affection seems genuine, but because the bacterium ravaged his facial nerves his expression is strained and his left eye is tearing. Like many with severe disabilities or who would be shunned if they returned to their villages, Gu has no interest in reintegrating into society. “This is my home,” he says.

  12. Bhutan

    Improbable Partners Aim to Bring Biotechnology to a Himalayan Kingdom

    1. Richard Stone

    A British mycologist and a local businessperson have launched a pharmaceutical venture grounded in a Buddhist reverence for the environment.

    Bhutan biopharma brain trust.

    Entrepreneur Wangdi Jamyang (left) and mycologist Nigel Hywel-Jones.

    CREDIT: R. STONE/SCIENCE

    THIMPU—In a quaint wooden house on a hill overlooking Bhutan's rustic capital, dozens of test tubes lie on a table bathed in the morning sun. “This is the worst way to store fungi,” growls Nigel Hywel-Jones. The mycologist and a pair of young apprentices cooked up the growth medium themselves—potato dextrose agar—by chopping up and boiling spuds and adding dextrose, antibiotics, and agar powder. They filled test tubes with the homebrew and set them in a slope to maximize the surface area for culturing fungi, some possibly new to science, that they collected in Bhutan's high country. It would have been better to keep the fungi frozen in suspended animation, but for now that's not an option, says Hywel-Jones, who is waiting for a −80°C freezer to arrive.

    The challenges of carrying out high-caliber science are daunting in an isolated country known for tracking its standard of living with a Gross National Happiness index. Hywel-Jones, a lab chief at the National Center for Genetic Engineering and Biotechnology (BIOTEC) in Bangkok, arrived here last September to help a biotech company take root in a land with a mere handful of Ph.D. scientists. “I was ready for a new challenge,” he says.

    Hywel-Jones, on a temporary assignment from BIOTEC, is serving as an adviser to Bhutan Pharmaceuticals Private Ltd. (BPPL), a company founded by local entrepreneur Wangdi Jamyang. Besides prospecting for fungi that attack insects and culturing isolates that may have medicinal value, Hywel-Jones is crafting a business model for biotech in the kingdom. There is no dearth of raw materials. Bhutan's highlands are a prime habitat for at least one prized commodity: an insect fungus, Cordyceps sinensis, that fetches outrageous prices as a Chinese medicine. Hywel-Jones believes that Bhutan, a biodiversity hot spot, may harbor a wealth of novel compounds for Western medicine, too. “There's fantastic potential,” he says. Wangdi puts it this way: “No one knows much about Bhutan, and that's a selling point: Brand Bhutan.”

    Long tradition.

    Biochemist Phurba Wangchuk examines ancient scrolls on medicinal herbs.

    CREDIT: R. STONE/SCIENCE

    The duo insists that they are not embarking on a biological Gold Rush. For starters, BPPL is collaborating with the government's National Biodiversity Centre and has approval for now to collect only Cordyceps and related species. (The company hopes to expand to other fungi and plants after Bhutan develops expertise in these areas.) Wangdi emphasizes that their activities will be guided by a Buddhist reverence for the environment enshrined in Bhutan's 2008 constitution, which calls for preserving 65% of the country as forest. “We want to set an example for future generations,” says Wangdi. “Look, just because we got approval to start exploring, we should not go in and exploit.”

    Some scientists commend the new venture. “It is generally the case that big pharma has stopped its search for anti-infectious drugs,” says Gary Strobel, a plant scientist at Montana State University, Bozeman, who travels the globe in search of fungi of potential commercial value. “There are promising life forms out there, but few people seem to be interested in finding and utilizing them,” he says.

    Blazing a trail for the pharmaceutical industry carries a moral responsibility to protect Bhutan's interests, Wangdi says: “We'd like to open Bhutan to the world—the right way.”

    Biological Shangri-La

    After a half-hour hike into a mixed broadleaf and pine forest in Dodena, north of Thimpu, Hywel-Jones and Wangdi break for lunch at a makeshift camp 2800 meters above sea level, the first station on an arduous 5-day trek to a Cordyceps research site nestled in a valley more than 5000 meters high. The fungus is used in China to treat many ailments, from flu to impotence; in Bangkok, Hywel-Jones and colleagues have isolated novel Cordyceps metabolites, including an anti-tuberculosis agent that they have patented. Wangdi passes out sandwiches and hands Hywel-Jones his “diet”: a bottle of Druk 11000, a local beer.

    They make an odd couple. Wangdi, 41, trim with short black hair and an easy smile, opened his latest money-spinner, a laminate factory near the border with India, last December. Long-haired and irreverent, Hywel-Jones, 51, has gained renown in Bhutan's upland villages for trekking in sandals through snow to his research site and surviving for days on crackers and Marmite. The two enjoy a playful, wry rapport.

    Long before their improbable partnership began, Hywel-Jones had been coming to Bhutan on brief research stints. He first came in 2002, invited by Tshitila (like some Bhutanese, he goes by one name), an agronomist with the agriculture ministry's Renewable Natural Resources Research Centre in Yusipang. Tshitila had asked Hywel-Jones to consult on an urgent fungal problem.

    Every spring, Himalayan villagers fan out by the thousands to dig up the few-centimeter-long fruiting bodies of C. sinensis, along with the husks of the ghost moth caterpillars that the fungus ghoulishly devours. Known as yartsa guenbub in Bhutan, the finest Cordyceps fetches several thousand dollars per kilogram (Science, 21 November 2008, p. 1182).

    Going once.

    … Buyers examine Cordyceps before an auction; prime specimens fetch astronomical prices.

    CREDIT: N. HYWEL-JONES

    In 1995, a royal decree declared Cordyceps a protected species and forbade its collection. Research was permitted, however, and a decade ago, when Tshitila and his colleagues were out in the field, they increasingly encountered poachers from Tibet coming across the porous northern border to collect Cordyceps. Not surprisingly, that left Bhutanese villagers fuming. “I remember Tshitila's first e-mail asking if I could help with this problem,” says Hywel-Jones, a self-described “old-style, traditional taxonomist” who has named nearly 3 dozen fungal species. “I wrote back that I needed to see it firsthand. When he said ‘Sure,’” Hywel-Jones says, pumping his fist, “I said, ‘YES!’” He then had to consult an atlas to find out where precisely Bhutan is located.

    In their initial survey in the spring of 2002 in the Soe Valley, Hywel-Jones, Tshitila, and colleagues logged ample Cordyceps. They recommended that the government establish a research program on sustainable collection and legalize the harvest before the fruiting bodies shoot spores. “Our idea was that if locals were allowed to collect, they would put pressure on their Tibetan cousins not to collect,” Hywel-Jones says. In 2004, the ban on Cordyceps collection was lifted for 1 month every year, in June. That decision, says Wangdi, has pulled many rural Bhutanese out of poverty: Their earnings from Cordyceps can exceed a year's income from yak herding.

    With support from the U.K. government's Darwin Initiative, in 2005 Hywel-Jones and Tshitila established research plots at Nam Nha, in western Bhutan, that are monitored each year to track population levels and the effects of collecting. Meanwhile, BIOTEC has hosted Bhutanese researchers for training stints in Bangkok. In 2008, Hywel-Jones says, he met Wangdi, “and the rest is history.”

    Branding Bhutan

    In the library of the Institute of Traditional Medicine Services (ITMS) here, a young man wearing a gho, Bhutan's national dress, carefully unwraps a canary-yellow cotton cloth. Inside are long and narrow rectangular scrolls in jagged Dzongkha script. The ancient manuscript is a kind of medieval Merck Manual compiled when Bhutan was known as Lho Men Jong, or “Southern Land of Medicinal Herbs.”

    To Phurba Wangchuk, an ITMS biochemist who earned a master's degree in natural product chemistry from the Australian National University in Canberra, these scrolls are the guiding principles of Bhutan's health care strategy, which is to ensure access to high-quality, traditional Bhutanese medicine. ITMS trains practitioners and produces more than 100 preparations, including CordyPlus, a concoction based on Cordyceps and “other health-promoting ingredients,” says Phurba. ITMS's preparations include several dozen medicinal plants found only in Bhutan—organisms that are largely terra nova for Western scientists.

    One aim of BPPL is to zero in on active compounds. Phurba says that approach does not threaten ITMS, which focuses solely on traditional medicines for the Bhutanese market. In the long run, developing Western medicines by synthesizing compounds could prevent unsustainable exploitation of biological resources. For that reason, Phurba says, BPPL “is on the right track.”

    The road ahead is not easy. Phurba is one of a rare breed of Bhutanese with credentials in this field, notes Hywel-Jones, whose two assistants have no previous lab experience. “It's going to take time to build a research base,” he says. Toward that end, BPPL, in collaboration with the government, plans to send top students over-seas to earn bachelor's degrees in areas such as biochemistry and mycology, in which expertise would benefit the company and the nation. Hywel-Jones envisions that 15 years from now, BPPL could have 200 or more research staff.

    In the short term, survival will require cutting deals with foreign companies. “They will be getting access to biodiversity that's never been opened up before,” says Hywel-Jones, honing his sales pitch. “Only 500 species of fungi have been described in Bhutan, compared to 6000 species of higher plants. We know that there is six times more fungal bio-diversity as there is in plants. So there are many thousands of fungal species here that have not been characterized.” Hywel-Jones is “passionate and sincere”—and knows his stuff, says Roger Shivas, curator of Agri-Science Queensland's plant pathology herbarium in Indooroopilly, Australia.

    BPPL is in talks with Novozymes, a top producer of commercial enzymes in Bagsværd, Denmark, to sell isolates of insect fungi for operating cash and a potential royalty if an isolate were to have commercial value. Hywel-Jones hopes that in a few years, BPPL will have sufficient in-house expertise to screen isolates itself. That game plan suits Wangdi. “I'm investing in Dr. Nigel,” he says. “Bad mistake!” Hywel-Jones says with a grin.

    Back in the forest, Hywel-Jones, in the mode most people in Bhutan encounter him—wearing a T-shirt and sandals and downing a Druk 11000—says the adventure of launching a biotech industry in Bhutan came at just the right moment in his career. “In Thailand, I was stuck in the lab, writing reports and proposals for bean counters and stuff like that. Yet, this is where I'm happiest and most productive,” he says. “The best ideas come when you're in the forest.” He and Wangdi hope that more than a few new drugs will emerge from Bhutan's forests as well.

  13. JOINT MATHEMATICS MEETING, 13–16 JANUARY, SAN FRANCISCO, CALIFORNIA

    Politics as (Un)usual

    1. Barry Cipra

    At the Joint Mathematics Meetings, mathematical voting theorists described a recent case study that suggests different voting systems only rarely produce the vastly different results possible in theory.

    Politics, it's said, is the art of the possible. And for decades, mathematical voting theorists have pointed to the possibility that different voting systems—from simple plurality to instant run-off to the rank-ordered Borda count—could produce vastly different results. Donald Saari, director of the Institute for Mathematical Behavioral Sciences at the University of California, Irvine, and a leading voting theorist, likes to boast that if you tell him the result you want (say, for a textbook selection or a new hire for your department) and your voters' actual preferences, he'll find a perfectly fair way of guaranteeing the desired result.

    CREDIT: © AKIYOSHI KITAOKA 2009

    But how common are such paradoxes in practice? Not very, if a recent case study is typical. In a session on voting theory at the joint meeting of the American Mathematical Society and the Mathematical Association of America, Anna Popova, a graduate student in psychology at the University of Illinois, Urbana-Champaign, described an analysis of ranked ballots from 8 years of voting for the presidency of the American Psychological Association (APA). She and her adviser, Michel Regenwetter, found that different voting methods gave the same result much more often than not.

    One classic voting paradox is known as a Condorcet cycle. An extreme example occurs when a third of the voters prefer Alice to Bob to Cathy, another third prefer Bob to Cathy to Alice, and a final third prefer Cathy to Alice to Bob. In such a case, an outright majority prefers Alice to Bob, a different outright majority prefers Bob to Cathy, and yet another outright majority prefers Cathy to Alice. Subtler examples, with the numbers not exactly equal, produce cases in which a reasonable argument can be made—and a voting system adopted—for electing any of the candidates.

    Who's on first?

    Optical illusion (left) mimics a paradoxical “everybody wins” outcome that can actually occur in ranked-choice voting.

    Popova and Regenwetter obtained data sets from APA elections from 1998 to 2005, each with upward of 20,000 voters giving full or partial rankings to five candidates for president. (APA uses a form of instant-runoff voting, in which candidates with the fewest first-place votes are successively eliminated and their supporters' ballots are redistributed to those voters' second-place selections.) The research, which compared seven different voting methods, turned up no examples of Condorcet cycles and found only one case in which one method (plurality vote) produced a different winner from the others.

    Steven Brams, a voting theory expert at New York University in New York City, questions the generality of the psychologists' findings, noting that balloting in professional societies is often heavily influenced by the process of selecting nominees. “I don't allege that its nominating committees pick some preferred candidate and then fill in the rest of the ballot with weak opponents,” he says. “But it may be more than coincidence that one candidate almost always handily beats four opponents.” Saari is similarly unsure. “The only way such an empirical result can happen is if people have remarkably similar preferences, much more so than we would expect in general society,” he says.

    Regenwetter agrees there's a lot left to be explained. But it's becoming clear, he says, that “the empirical world is highly different from the picture that has generally emerged out of the mathematical theory of social choice.”

  14. JOINT MATHEMATICS MEETING, 13–16 JANUARY, SAN FRANCISCO, CALIFORNIA

    Perfection in a Box

    1. Barry Cipra

    At the Joint Mathematics Meetings, researchers reported the first sighting of a "perfect parallelepiped," a brick whose sides are allowed to be parallelograms rather than strict 90º rectangles and all 13 of whose edges and diagonals are exact integers.

    Here's a good way to keep mathematicians busy for centuries: Make up an object, call it “perfect,” and then try to find out if it exists. Take so-called perfect numbers: whole numbers such as 6 or 28, which equal the sum of their divisors (6 = 1 + 2 + 3; 28 = 1 + 2 + 4 + 7 + 14). It's hard enough to find ones that are even, but no one has ever spotted a single one that's odd.

    Things are even worse with “perfect cuboids”: rectangular bricks whose three different edges and four different diagonals (three on faces of the brick and one angling through its “body”) all have lengths that are exact integers. Nobody knows whether they exist at all. But something similar has just turned up: At the meeting, researchers reported the first sightings of “perfect parallelepipeds.”

    A parallelepiped is basically a brick whose sides are allowed to be parallelograms rather than strict 90° rectangles. Like a cuboid, a parallelepiped has three different edges, but it has 10 different diagonals: two on each of its three different sides, and four crisscrossing the body. Perfection is achieved if all 13 of these numbers are exact integers.

    A perfect 10.

    Can you find the 10 diagonals that make the parallelepiped at right as perfect as the labeled one at left?

    CREDIT: SOURCE: CLIFF REITER AND JORGE SAWYER

    Now Clifford Reiter of Lafayette College in Easton, Pennsylvania, and Jorge Sawyer, an undergraduate at Lafayette, have found the first examples of perfect parallelepipeds. Their search depended on a simple property of all parallelograms, established by simple algebra: The sum of the squares of a parallelogram's two diagonals is twice the sum of the squares of its two edges. With that formula and a bit of number theory to guide them, Reiter and Sawyer could easily run a systematic search for all parallelograms with edges of “short” integer length, say, into the thousands, whose diagonals are also integers. They then looked for combinations of these “perfect parallelograms” to serve as sides of candidate parallelepipeds and devised a computer algorithm to pick out the perfect ones.

    “The biggest surprise for me was how quickly we got results,” Sawyer says. Their first example has edges of length 271, 106, and 103 (see figure, left). In all, the computer search found 30 perfect parallelepipeds, with edge lengths up to 3920. Some are tantalizingly close to being cuboids, with one or two rectangular sides. Such findings “may spark even more interest in the perfect cuboid problem,” Sawyer says.

    Ezra Brown, a number theorist at Virginia Polytechnic Institute and State University in Blacksburg, agrees. “The size of Reiter and Sawyer's smallest solution is very surprising,” he says. “Apparently, easing the restrictions that the faces be rectangles is more crucial than anyone thought.” Nonetheless, he notes, perfect cuboids, if they exist at all, are a long way off: Computers have looked at all possible bricks with edge lengths up to 10 billion without finding a single one that's perfect.

  15. JOINT MATHEMATICS MEETING, 13–16 JANUARY, SAN FRANCISCO, CALIFORNIA

    What Comes Next?

    1. Barry Cipra

    One of mathematicians' most beloved Web sites is getting ready for a makeover, it was reported at the Joint Mathematics Meetings. The Online Encyclopedia of Integer Sequences, established by Neil Sloane at AT&T Labs Research in 1996 and run largely as a one-man shop, is poised to go "wiki," with 50 associate editors taking over much of the workload.

    One of mathematicians' most beloved Web sites is getting ready for a makeover. The Online Encyclopedia of Integer Sequences, established by Neil Sloane at AT&T Labs Research in 1996 and run largely as a one-man shop, is poised to go “wiki,” with 50 associate editors taking over much of the workload.

    The OEIS, or simply “Sloane” as it's known to sequence fanatics, is a database of nearly 200,000 lists of numbers—a mathematical equivalent to the FBI's voluminous fingerprint files. Much as fingerprints give police a quick way to link a new crime to earlier ones, sequences enable researchers to make connections between mathematical problems that might otherwise go unnoticed. The innocuous-seeming sequence 1, 2, 5, 14, 42, 132, …, for example, arises in a huge number of different contexts, from counting the arrangements of nonintersecting chords inside a circle to enumerating secondary structure possibilities of RNA. To sequence fanatics, such “Catalan numbers,” as they're known, are even more famous than the ubiquitous Fibonacci sequence 1, 1, 2, 3, 5, 8, 13, … .

    Chewy.

    Database managed by Neil Sloan (top) includes the “toothpick” sequence (1, 3, 7, 11, 15, 23, 35,…), shown here in color-coded steps.

    CREDIT (PHOTO): SUSANNA CUYLER

    Sloane began compiling sequences in 1965 as a graduate student at Cornell University. By 1973 he had 2372 of them, which he published as A Handbook of Integer Sequences. An updated edition, with 5487 sequences, appeared in 1995, with the help of Simon Plouffe of the University of Quebec, Montreal. But by then, Sloane was already moving online. The OEIS made its debut a year later, with a database of 10,000 sequences.

    The OEIS “is one of the most useful tools available online for the working mathematician,” says Doron Zeilberger, a combinatorialist at Rutgers University, New Brunswick. “It also is a great tool for determining the novelty of a new sequence. If it is not in Sloane, it is most likely to be new!”

    The Web site invites users to submit new sequences or comment on existing ones. Such contributions have fueled the database's steady growth. In 2009 alone, the total increased by 18,709 sequences, or more than 50 a day. “Sequences are still pouring in,” Sloane says.

    Even as he edits the constant stream of new sequences, Sloane takes time to admire some of the contributions. His latest favorite is the “toothpick sequence,” added in 2008 by Omar Pol, an OEIS contributor from Buenos Aires. The toothpick sequence registers the increasing size of a geometric arrangement of toothpicks, in which a new batch is added at each stage, centered on and at right angles to the exposed tips of the previous batch (see figure). The picture that emerges displays surprising fractal growth. “It's got beautiful structure,” Sloane says. He and his AT&T colleague David Applegate have written a paper on the sequence's mathematical properties, and Applegate has contributed a movie of its geometric growth, linked to its entry in the OEIS.

    Sloane set up the OEIS Foundation last year and transferred intellectual-property rights to the nonprofit organization. With Applegate's help, he plans to move the database to a wiki format, giving each sequence its own Web page, with new submissions moderated by a board of editors. The transition has hit a snag, however: Search-engine software in the “wikiverse” can't yet handle sequences of numbers.

    Once that technicality is overcome, Sloane expects the wiki format to be an improvement. “It's the correct mechanism for handling the database,” he says. As for his anticipated reduced workload, “it'll mostly be a relief. On the other hand, I'll miss all the e-mails.”

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