# News this Week

Science  23 Jul 2010:
Vol. 329, Issue 5990, pp. 374
1. HIV/AIDS

# At Last, Vaginal Gel Scores Victory Against HIV

1. Jon Cohen

Goooooal! While South Africa was in the spotlight for hosting the World Cup games, its AIDS researchers were quietly preparing for an announcement of a major milestone in their field: For the first time ever, a vaginal gel has unequivocally blocked the transmission of HIV.

In a trial that involved nearly 900 South African women, those who received a vaginal gel that contains an anti-HIV drug had a 39% lower chance of becoming infected by the virus than those who received a placebo. “It is the first time any biological intervention against HIV-1 transmission has ever shown convincing efficacy in a large trial,” says John Moore, who studies similar vaginal microbicides at the Weill Cornell Medical College in New York City. “It's a clear-cut result with obvious protection at a meaningful level.”

More than 30 randomized, controlled studies of microbicides, vaccines, and drugs to date have failed to thwart sexual transmission of HIV or have yielded such marginal success that researchers wound up hotly debating the data for years after the trials were complete. But there's no ambiguity about the data from this new microbicide study reported online in Science this week (www.sciencemag.org/cgi/content/abstract/science.1193748) and in a presentation at the 18th International AIDS Conference in Vienna: Of the 444 women who received a placebo gel, 60 became infected with HIV versus 38 infections in the 445 women who received the microbicide. The result was statistically significant, and no serious side effects occurred. “It's a moment we've been waiting for 2 decades,” says epidemiologist Quarraisha Abdool Karim, who, with her husband, Salim Abdool Karim, headed the study, known as CAPRISA 004.

The study began in May 2007 and enrolled sexually active women between the ages of 18 and 40 who attended clinics in KwaZulu-Natal, South Africa, an area that has an extremely high rate of new HIV infections in young females. Researchers randomly assigned the women to receive either an inert gel or the gel mixed with the anti-HIV drug tenofovir for 30 months. Participants were asked to insert the gel within 12 hours before and after having sex. They were also provided with condoms and HIV-prevention counseling.

The women reported their sexual activity each month, and the researchers also collected used gel applicators—181,340 to be exact—to monitor adherence. On average, women used the gel as advised nearly three-fourths of the time. Subset analyses showed, as expected, that the women who used the gel most frequently had the most protection: In a group of 336 “high adherers” who used the gel as advised more than 80% of the time, the reduction in risk of infection over 30 months jumped from the 39% found in the entire group to 54%. In the group that used the gel less than half the time, the risk reduction plummeted to 28%. The study also found that adherence dropped over time; among the entire group, the gel reduced the risk of infection by 50% over the first 12 months versus 39% over 30 months. “Task number one is better adherence,” says Salim Abdool Karim, also an epidemiologist and the head of the Durban, South Africa–based CAPRISA, which stands for Centre for the AIDS Programme of Research in South Africa.

Both the CAPRISA investigators and other researchers who were not involved with the study stress that these results do not mean that a tenofovir microbicide gel is ready for market. “It's a really exciting first step,” says Sharon Hillier, a reproductive specialist at the University of Pittsburgh in Pennsylvania, who heads the Microbicide Trials Network sponsored by the U.S. National Institutes of Health. Earlier microbicide studies had all used compounds that attacked HIV nonspecifically, using surfactants and the like, she notes. “We got a proof of concept: Topically applied antiretrovirals can interrupt HIV in women. Is it good enough? Absolutely not. We want to see something more effective.” Hillier and others also say they would like to see the CAPRISA 004 results confirmed in a second study.

Hillier is heading just such a trial. Called Vaginal and Oral Interventions to Control the Epidemic (VOICE), the study is comparing two types of pre-exposure prophylaxis: daily vaginal application of a tenofovir gel and oral administration of an anti-HIV drug. (It is testing both tenofovir and a sister compound, Truvada.) VOICE, begun in September 2009, is expected to run for 4 years and enroll 5000 women in South Africa (the Abdool Karims are collaborators) and three other countries in southern Africa. “It's going to be important to have data from more than that very high incidence single site, and it's important to see if we can do better with more frequent dosing of the gel,” says Hillier. Other microbicide researchers are exploring what they believe are more potent anti-HIV drugs than tenofovir and simpler delivery methods like vaginal rings that periodically secrete the compounds.

Even if oral pre-exposure prophylaxis works, many researchers believe a microbicide gel could have many benefits for women. For one, only minimal amounts of the drug make it to the blood system, reducing the risk of side effects. Salim Abdool Karim further stresses that prevention strategies, just like contraception options, are not one size fits all.

The next step for the CAPRISA researchers is to analyze why some women who received the tenofovir gel still became infected. “What undermined tenofovir's ability to protect some of those women?” asks Salim Abdool Karim. “We need to go back into the lab and understand why we didn't see a better effect to find potential avenues to try and do better.”

2. Drug Safety

# Planned Study of Avandia in Doubt After FDA Review

1. Sam Kean

Since 2007, controversy has swirled around whether the glucose-lowering drug Avandia increases the risk of heart attacks in diabetes patients. The effect, if real, is modest at most. And last week, a committee of 33 top diabetes experts reviewing whether the Food and Drug Administration (FDA) should pull Avandia from the U.S. market couldn't render a clear verdict, either. Twelve voted to withdraw the drug; 10 said that its use should be restricted; and the remainder wanted it to stay on the market, but perhaps with more warnings.

That decision, which left consumers and doctors hanging, also left a lingering scientific question: What should happen to a study, called TIDE, that compares Avandia and a competing drug, Actos? The double-blind, randomized study, which got under way last year, is supposed to provide what earlier, lower-quality studies don't: a clear assessment of Avandia. The drug's manufacturer, GlaxoSmithKline, supported a large, recent study that found no increased heart-attack risk. But this study, called RECORD, was not blinded, and scientists at the FDA hearing impugned both RECORD's quality and integrity. TIDE, which is meant to enroll 16,000 diabetes patients in 39 countries in a 6-year study, was designed to remedy the problem. But now it is running into trouble itself.

The principal investigator, Hertzel Gerstein, a doctor at the Population Health Research Institute at McMaster University in Hamilton, Canada, explains the challenge. Some studies suggest that Avandia reduces cardiovascular disease, and others suggest that the drug increases the risk. “If you listen to much of the evidence,” he adds, “the answer is very simple: We don't know.” (Glaxo, a TIDE sponsor, approached Gerstein about doing TIDE and still provides input. But Gerstein's team collects the data and controls the analysis.) Twenty scientists on the FDA committee agreed with Gerstein, including Morris Schambelan, a doctor at the University of California, San Francesco. “Most of the people felt that, if the drug did stay on the market, we need more safety data,” Schambelan says—data TIDE could provide.

But a dozen other members heard the same evidence and voted to kill TIDE because they saw it as either flawed or coming too late. One concern is about informed consent. Studies show that Actos, which has been on the market since 1999, provides the benefits of Avandia without the same risk—one reason that a few members said they felt comfortable voting to pull Avandia. But if Actos is benign, some scientists argued that TIDE amounts to a test of whether Avandia harms people—a dubious proposition. Ruth Day, who does research at the Medical Cognition Laboratory at Duke University in Durham, North Carolina, on how well people grasp informed-consent documents, said, “I do not believe that any participants in the study as currently set up will understand what they're getting into.”

Another concern cited by FDA advisers is timing. William Knowler, a diabetes epidemiologist with the National Institute of Diabetes and Digestive and Kidney Diseases, said at the hearing, “Although I'd like to have the results of the TIDE study, I think at this point it's not ethical to wait another 5 or 10 or whatever years it takes to get that and leave the drug on the market.” And that assumes that TIDE can sign up enough patients. So far, TIDE has enrolled 1120 people—less than one-tenth of the goal—in 23 countries.

Gerstein acknowledges that it could be difficult to complete TIDE if FDA pulls Avandia. India recently asked Glaxo to suspend TIDE in India pending FDA's decision. A Glaxo spokesperson said TIDE is moving ahead as planned. FDA declined to comment on when it might decide Avandia's fate. Regardless, worldwide sales of Avandia have already dropped by 56% since 2006.

Drug experts are being pulled in opposite directions by the Avandia case. Medicine's imperative—first, do no harm—may be at odds with the scientific tenet: When in doubt, collect more data. As FDA ponders what to do, it has issued a mandate designed to avoid similar messes in the future: All new glucose-lowering drugs must be tested in large, postmarket studies for cardiovascular risk. But that doesn't help clear up the status of Avandia—and it may not save TIDE.

3. Undergraduate Education

# NSF Misfires on Plan to Revamp Minority Programs

1. Jeffrey Mervis

Everybody agrees that U.S. colleges and universities need to prepare more minority students to enter careers in science and engineering. But almost nobody likes a new plan by the National Science Foundation (NSF) to fold three programs aimed at achieving that goal into a still-to-be-defined initiative. Scientists and university administrators involved in the programs are up in arms, and Congress is telling NSF to go back to the drawing board.

NSF currently spends $90 million a year on three efforts tailored to institutions that serve African Americans and American Indians: the Louis Stokes Alliance for Minority Participation (LSAMP), the Historically Black Colleges and Universities Undergraduate Program, and the Tribal Colleges and University Program. Last year, a U.S. House of Representatives spending panel told NSF to design a fourth program specifically for the nation's Hispanic population, the nation's largest underrepresented minority. That step could quadruple the pool of eligible minority-serving institutions. At the same time, as part of a larger campaign to eliminate redundancy in government, budget officials in the Obama Administration began urging NSF to streamline its stable of programs aimed at increasing the participation of underrepresented minorities in so-called STEM (science, technology, engineering, and mathematics) fields. In an attempt to resolve the conflicting guidance, NSF requested a bit more money—$103 million—in its 2011 budget for a new initiative that it awkwardly labeled Comprehensive Broadening Participation of Undergraduates in STEM. “We felt we had reached a plateau in college graduation rates, in Ph.D. production, and in transition to the professoriate,” says James Wyche, who headed the NSF division that runs the three minority programs before becoming provost of Howard University in Washington, D.C., earlier this year. “So the question was, do you stay the course or look for something else?”

The specific suggestion to combine programs came from the White House, he adds. “OMB [The Office of Management and Budget] encouraged us to think about a program that would consolidate what we were doing to broaden participation among the targeted groups, something that would use the best practices from each one.”

The bare-bones budget announcement, unveiled in February, didn't provide any details. In May, NSF issued a 5-page concept paper (http://www.nsf.gov/od/broadeningparticipation/bp.jsp) that declared the existing programs “should serve as a foundation for a new approach,” meaning they would be dissolved. It also said that Hispanic-serving institutions, a poorly defined term for schools at which Hispanic students constitute a significant share of the overall enrollment, would be invited to seek funding. Major research universities, now partners in some existing projects run by minority-serving institutions, would be eligible to apply directly to NSF as the lead institution.

Although the paper asks for advice on how to proceed, the community had heard enough to ring the alarm. For openers, say critics, the three programs are working: Outside evaluations confirm that they are attracting and graduating more minority students. The programs have also developed an approach that can be scaled up. So university administrators say they don't understand why NSF would want to dilute them.

Opponents of the NSF plan also attacked the inclusion of the nation's top research universities. That change would not only open the door to institutions with a poor track record of training minorities in science and engineering fields, they said, but also give those schools an advantage because of their vastly superior resources. Finally, critics complained, NSF hadn't offered any evidence that a different approach to training minority scientists would work better.

Last month, the 42 consortia in the LSAMP program told NSF they strongly oppose the changes. Stephen Cox, provost of Drexel University in Philadelphia, Pennsylvania, and director of a project involving nine local and regional institutions, says he also wonders why NSF has put the burden for broadening participation in science on these three, relatively tiny, programs. “Rather than squeezing more blood from this stone,” Cox said, “why doesn't NSF get some more stones?”

Congress doesn't care much for NSF's new idea, either. This spring, the House of Representatives, as part of its reauthorization of the America COMPETES Act that covers NSF's research and education activities (H.R. 5116), told NSF to keep the three programs intact in 2011 and submit a report “clarifying the objectives and rationale for such changes” before heading off in a new direction. “It's something they had not discussed with us,” says Representative Eddie Bernice Johnson (D–TX), a senior member of the House science committee, who crafted the language on the minority programs. “I think they need to discuss it with stakeholders, who told me that it seems like a way to cut a lot of money from these programs.” A Senate version of the reauthorization bill introduced last week (S. 3605) would also preserve the programs, and a House spending bill for 2011 likewise tells NSF to keep funding them.

NSF appears to be rethinking its strategy. Joan Ferrini-Mundy, acting head of NSF's education directorate, which oversees these programs, says NSF is looking hard “at what a transition would actually look like. A lot is still on the table.” She also notes that “broadening participation is an NSF-wide commitment” and that any final plan is likely to involve the agency's six research directorates as well.

4. Rare-Earth Elements

# Chinese Policies Could Pinch U.S. Efforts to Make Electric Vehicles

1. Robert F. Service

Last week, President Barack Obama high-lighted his commitment to clean-energy jobs by visiting the last of nine battery-manufacturing plants to be funded from last year's massive economic stimulus package. Speaking at a groundbreaking ceremony for a Holland, Michigan, company that will build lithium-ion batteries for future electric cars and gas-electric hybrids such as the Chevy Volt, Obama declared that the plant “is a symbol of where Michigan is going, … of where Holland is going, … of where America is going.”

That is, unless it runs into a Chinese brick wall.

This month, China announced that it will cut exports this year of rare-earth elements (REE) by 40%, leaving demand outside China exceeding the supply for the first time ever. Combined with Chinese export tariffs of 10% to 25%, the policy could ground fledgling efforts to build clean-energy industries in the United States and other Western countries. “It will just be untenable to compete” with companies based in China, says Jeffrey Green, president of J. A. Green and Co., a government-relations firm in Washington, D.C., specializing in rare earths.

China currently produces more than 97% of all rare earths, a group of 17 elements consisting of scandium, yttrium, and the 15 lanthanides. They are vital for a host of electronics and green-energy technologies, and their use is expected to triple between 2000 and 2014, topping 200,000 metric tons. But despite rising global demand, China has focused increasingly on domestic needs.

In response, the United States and other countries are gearing up for production. Molycorp Minerals in Greenwood Village, Colorado, for example, is expected to reopen its mine in Mountain Pass, California, in 2012. But that mine's annual output of 20,000 metric tons a year won't fill the gap left by lower Chinese exports.

That gap could spell trouble for the Obama Administration's plans to develop electric vehicles. In recent years, the U.S. Department of Energy (DOE) has spent roughly $5 billion on projects to promote electric-vehicle technologies, including nine battery-manufacturing plants and 11 electric drive component-manufacturing facilities. Last week, DOE said that by 2015 these investments would give the country the capacity to produce up to 40% of all advanced batteries manufactured globally for electric vehicles. Last year, the U.S. share was 2%. Most of the new advanced batteries are slated to be lithium-ion batteries, which do not require rare earths from China. Even so, lithium is mined in only a few countries, which has also prompted concerns about supply shortages. And current hybrid-car batteries typically include more than 10 kilograms of lanthanum, the lightest of the rare earths. Although one of the most abundant rare earths, lanthanum could be hardest hit by China's new export controls, which cap overall exports. Observers worry that companies, to increase profits, may try to export more high-value REEs, such as dysprosium and terbium, and drastically reduce lower-value elements such as lanthanum. That change, in turn, could result in price hikes for some elements. To counter the advantages enjoyed by Chinese companies, U.S. companies that make magnets and other high-tech components want Congress to set up loan guarantees to back domestic mining, processing, refining, purification, and metals production of rare earths. Bills have been introduced in both houses, but no action is expected in the current session. 5. ScienceInsider # From the Science Policy Blog Climate scientist and activist Stephen Schneider, 65, died 19 July of an apparent heart attack. His death ends a nearly 40-year career doing climate science, assessing climate science for policymakers, explaining it articulately to the public, and defending it energetically against skeptics. A spending panel in the U.S. House of Representatives voted to give DOE's Office of Science next year only what it received this year, erasing a$221 million increase requested by the Obama Administration. The National Institutes of Health did a bit better from a sister panel, receiving its full request: a $1 billion bump from its current$31 billion budget.

A federal judge has dismissed charges against four animal-rights activists accused of harassing researchers at two University of California campuses in 2007 and 2008. But prosecutors could file new charges.

A provocative new analysis suggests that illegal logging has declined 22% worldwide since 2002, thanks to stricter government policies and enforcement. Some experts are skeptical of its conclusions, however.

More than 2200 Russian researchers have petitioned the government asking it to consult with the scientific community when making major science-policy decisions.

The Royal Society and the British Academy have strongly warned the British government that looming cuts to science funding could be “irreversibly catastrophic for the future of U.K. science and economic growth.”

A committee of the National Research Council has provided the latest and most quantitative estimates yet of how the coming global warming could affect the world. The picture hasn't gotten any prettier.

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

6. Conservation Biology

# Last Stand on the Yangtze

1. Richard Stone

SHISHOU, CHINA—A hundred meters or so off the bow of our motorboat, a dark shape breaks the surface and quickly vanishes. Was it a trick of the light? Heavy rains have washed nutrients into the lake, turning the usually clearer waters emerald green. A few minutes pass, then ecologist Xie Songguang, perched like a coxswain, points off starboard and cries: “Over there!” The earlier sighting was no mirage: Two more glistening humps slice through the waves.

The Yangtze finless porpoises in Tian-E-Zhou Oxbow Nature Reserve, near the town of Shishou, dare not approach; too many of their kind have perished in encounters with humans. The world's only freshwater porpoise is down to fewer than 1800 individuals, less than half the estimated population a decade ago. A few dozen porpoises live under the watchful gaze of rangers in Tian-E-Zhou, an oxbow lake that once was a 21-kilometer-long section of the Yangtze River. But time is running out: Unless threats to its survival are met head on, the porpoise could be gone in 15 years, says Wang Ding, an ecologist at the Institute of Hydrobiology (IHB) in Wuhan.

The finless porpoise is an icon of an ecosystem under siege. The Yangtze, the world's third longest river, faces manifold threats, including overfishing, heavy boat traffic, and habitat fragmentation due to hydropower projects such as the mammoth Three Gorges Dam (Science, 1 August 2008, p. 628). Two charismatic animals—the Yangtze river dolphin, or baiji, and the Chinese paddlefish, a titan that once reached 7 meters in length—are down to a handful of individuals or have already gone extinct.

The loss of such top carnivores is an early sign of ecosystem collapse, says David Dudgeon, an aquatic ecologist at the University of Hong Kong. Adding insult to injury, Yangtze fishing communities have already begun to forget that these creatures even existed, Samuel Turvey of the Institute of Zoology in London and colleagues report in the June issue of Conservation Biology. “I was extremely surprised that local ‘community memory’ of the Yangtze megafauna is being lost so rapidly,” Turvey says.

Researchers hope to make a last-ditch effort to stabilize the Yangtze ecosystem and prevent further extinctions. IHB is working with China Three Gorges Dam Corp. to set up a reserve in the dam's reservoir, and Honghu Xin-Luo National Baiji Reserve plans to launch a finless porpoise ex situ conservation program. Meanwhile, influential researchers are calling for a lengthy fishing moratorium for the entire Yangtze. “If we can't control overfishing, all other approaches will fail,” says IHB's Xie.

## Troubled waters

The IHB researchers know all too well what it's like to watch a species fade into oblivion. In 1978, IHB ecologist Chen Peixun was tapped to form a baiji study team. Within months, the team deduced that the species was in trouble—“and that it would go extinct if we didn't do anything,” Chen says. She puts the blame squarely on human activity. During the 1990s, about 40% of known baiji deaths were caused by illegal electric fishing gear. Many animals also died from run-ins with ships, and others were killed when sandbars—a favorite hangout for cetaceans—were blasted for easier navigation.

IHB researchers gleaned what they could from a captive male baiji named Qiqi. The aim was to understand the creature well enough to transfer rescued animals to Tian-E-Zhou, which in 1992 was designated a national preserve for baiji and finless porpoises. But it was too late for the baiji. Yangtze surveys charted a decline from 11 sightings in 1997 to two in 1999. Then in 2002, Qiqi died of old age, apparently. That was the last baiji Chen and other scientists laid eyes on. In 2006, not a single baiji was spotted in an exhaustive survey, making it the first human-caused extinction of a cetacean (Science, 22 December 2006, p. 1860).

Several measures may avert a similar fate for the Yangtze porpoise. More sanctuaries could help, for starters. The porpoises reproduce readily in Tian-E-Zhou: In 2008, all five mature females there gave birth. But small reserves can become a death trap. In early 2008, unprecedented in recent memory, much of Tian-E-Zhou's surface froze over for 2 days. Five porpoises asphyxiated, including three pregnant females. “If the ice had lasted much longer, all the porpoises would have died,” says IHB's Hao Yujiang.

Food supply is another constant worry. Tian-E-Zhou is 250 kilometers east of Three Gorges Dam. Before 2003, when the reservoir behind the dam began to fill, the lake's connection to the Yangtze lasted the whole rainy season, from May to October. Now, that flow occurs only during the rainiest months of June and July. A too-brief connection suppresses fish spawning, says Hao, so researchers must stock Tian-E-Zhou with fish for the porpoises to eat.

Elsewhere, the main threats to the porpoise are overfishing, which reduces food supply, and the illegal use of nets slung across the river, which ensnare the mammals. Yangtze fish stocks have plunged since the 1950s, possibly limiting the porpoise's recovery, says Dudgeon. The key to survival may be a blanket fishing moratorium. At a workshop in Chongqing last September, IHB's Cao Wenxuan, one of China's most esteemed fish specialists, called for a 10-year fishing ban for the whole Yangtze. That would be feasible, Wang argues, because the 100,000 tons of fish hauled from the Yangtze each year is less than 1% of China's freshwater production, including aquaculture.

There is no sign that authorities are ready to take such a step in the near future. That riles Dudgeon, who penned a requiem for Yangtze ecology in the March/April issue of Aquatic Conservation. “How many icons do we need to lose?” he asks.

7. ScienceNOW.org

# From Science's Online Daily News Site

Will IVF Work for You? For couples who have trouble conceiving, in vitro fertilization (IVF) is often the last resort. Now researchers say they have come up with a way to better quantify a couple's chance of having a child using IVF.

A woman's age is an important factor in determining whether a couple will become pregnant, but it's far from the only one. So Mylene Yao of Stanford University School of Medicine in Palo Alto, California, and colleagues collected data on 20 variables that influence the success of IVF. These included age, number of previous pregnancies, and sperm count, and figures known after the completion of the first round of IVF, such as whether there was fertilization, endometrial thickness, and average number of cells per embryo. In all, the team fed data on more than 1600 first rounds of IVF into a computer model called a boosted tree.

When the researchers compared the model's predictive powers with a model based on age alone, they found that it was significantly more accurate in gauging success in the second round of IVF, they reported in the Proceedings of the National Academy of Sciences. In the future, such a model could help women decide whether to continue using IVF or whether to move on, experts say.

Why Gorillas Play Tag A new study of gorillas at play indicates that the animals know the limits of their social status—and that they play tag to help even the score.

Behavioral biologist Marina Davila Ross of the University of Portsmouth in Hampshire, U.K., and colleagues watched videos collected over 3 years of gorillas at various zoos and reserves in Europe. During play, some gorillas hit their playmates and ran away. Ross's team noticed a pattern in this game of tag: Gorillas lower on the social ladder were usually the taggers. These gorillas were also twice as likely to instigate another round of the game, and they frequently bared their teeth—a possible indication that they were willing to bite the other gorilla, the team reported in Biology Letters.

The findings, Ross says, suggest that low-status gorillas use the game as a sort of ego boost. And that means that gorillas are aware of inequities in their society, Ross says, marking the first time that such cognition has been observed in gorillas in a nonexperimental setting.

A Jupiter-Sized ‘Comet’ Comets aren't the only celestial bodies with long, glowing tails. A star 153 light-years from Earth is blowing away the atmosphere of planet HD 209458b, creating more or less the same effect. According to observations by NASA's Hubble Space Telescope reported this month in The Astrophysical Journal, the gas giant circles so close to its sun (an orbit of 3.5 days compared with Mercury's 88) that solar winds are slowly roasting it out of existence, causing its outer gases to evaporate into space. The planet, which is only slightly smaller than Jupiter, isn't going to disappear anytime soon, however: Researchers estimate it will take a trillion years before HD 209458b is completely vaporized. That's about 100 times as long as the universe has been around.

Reprogrammed Cells Remember Like a Texan who keeps his drawl after moving to California, induced pluripotent stem (iPS) cells—adult cells reprogrammed to resemble embryonic cells—retain signatures of the tissue from which they came, according to two new studies.

George Daley of Children's Hospital in Boston and colleagues tried to make blood from different types of iPS cells. iPS cells derived from connective tissue cells didn't work, but ones reprogrammed from blood cells made plenty of blood. The reason may be that each iPS cell line sports DNA methylation, a molecular coating on the DNA that turns genes on or off, that is typical of the cell type it came from, the team reported in Nature.

In a related paper in Nature Biotechnology, Konrad Hochedlinger of the Harvard Stem Cell Institute and his colleagues found that they could identify the origin of different iPS cell lines by simply looking at their gene expression. The differences gradually disappeared as the stem cells continued to replicate in the lab, so reprogramming adult cells seems to be a gradual process, Hochedlinger says. Both studies add to the growing evidence that reprogrammed cells are not exactly like traditional stem cells derived from embryos.

Read the full postings, comments, and more at news.sciencemag.org/sciencenow.

8. Newsmaker Interview

# Nobelist Paul Nurse to Pilot Royal Society, London Superlab

1. Jocelyn Kaiser

NEW YORK CITY, NEW YORK—In the late 1980s, working on yeast genetics experiments that would lead to a Nobel Prize, researchers in Paul Nurse's lab in Oxford, U.K., faced an unusual initiation rite: a ride in a two-seater glider piloted by their boss. The trip usually involved Nurse turning the dual controls over to his passenger, recalls his former postdoc Christopher Norbury, now a molecular biologist at the University of Oxford. “I loved it,” but, Norbury tactfully notes, “a small minority didn't enjoy it so much.” Nurse himself seemed to fear nothing, Norbury says.

Nurse, now the president of Rockefeller University in Manhattan, still flies; his latest outings are in a 1934 Boeing Stearman biplane with an open cockpit. And his fearlessness apparently remains intact, as he has recently agreed to leave Rockefeller to take on two of the highest-profile jobs in British science. Earlier this month, he was confirmed as president elect of the Royal Society, the U.K. scientific society founded 350 years ago. And last week, Nurse took on another challenge, agreeing to be the founding director and chief executive of the UK Centre for Medical Research and Innovation (UKCMRI). When it is up and running 5 years from now with 1500 researchers and staff members, it will be the largest research institution in Europe.

Leszek Borysiewicz, chief executive of the U.K. Medical Research Council, which is funding the majority of UKCMRI, calls the founding director position “perhaps the most important [science] job in Europe.” And it's one that will need a steady pilot, given that UKCMRI is being born out of a controversial decision to relocate the MRC's legendary National Institute for Medical Research (NIMR) from its suburban Mill Hill campus outside London to the city center (Science, 14 December 2007, p. 1704). Many onlookers consider the NIMR move—which merges resources from Cancer Research UK, the Wellcome Trust, and University College London—a big gamble. It will tie up £600 million, or nearly a billion U.S. dollars, at a time when British science may be facing the toughest financial crisis in 2 decades.

For the past 2 years, Nurse has chaired the UKCMRI scientific planning committee, an appointment respected even by those critical of the decision to close NIMR. And although he has outlined a vision for the planned lab, many details remain unclear, including how many NIMR scientists will make the move to London (Science, 11 December 2009, p. 1468).

Although Nurse, 61, was an obvious candidate to become the facility's first director, he originally told some people that he wasn't interested. He says he changed his mind when he learned about 6 months ago that the Royal Society planned to nominate him as president. The 5-year presidency is unpaid and only half-time; the UKCMRI directorship, a 5-year planning position, will also be half-time. “I did need another position” besides heading the society, he explains, and the two jobs make for “a complete package.” He becomes Royal Society president on 1 December and joins UKCMRI on 1 January.

The twin appointments are the capstone to a career full of unlikely twists. Nurse was born into a working-class family; his father was a mechanic, his mother cleaned houses in northwest London. There were “hardly any books at home,” he says, yet he became fascinated with science by the age of 8, when he watched the Sputnik 2 spacecraft flying above London. After secondary school, he was initially rejected from universities because of the language requirement—he flunked a French exam several times. Luckily, a professor negotiated an exception.

After graduate school in biochemistry, he switched to yeast genetics and cell biology. Later at the London labs of the Imperial Cancer Research Fund (ICRF), a U.K. charity, and at the University of Oxford, his group discovered an enzyme that controls yeast cell division, known as a cyclin-dependent kinase, and showed that humans share the same gene for this enzyme. Because cancer involves uncontrolled cell division, the finding had implications for understanding human cancer. The work garnered Nurse the 2001 Nobel Prize in physiology or medicine with Tim Hunt and Leland Hartwell.

Although he's never stopped doing research, Nurse became head of ICRF in 1996 and oversaw a sensitive merger with another cancer charity to create today's Cancer Research UK. In 2003, after the merger, he relocated across the Atlantic to become president of Rockefeller. There “he really changed the atmosphere in a number of ways,” says Princeton University molecular biologist David Botstein, a member of the Rockefeller board: Nurse made decision-making more transparent and inclusive of junior faculty members. He also recruited new faculty based primarily on their qualifications and not because they worked in a particular discipline, an uncommon approach, Botstein says.

Already a highly visible public figure in Britain, where he is a regular guest on the BBC (The Sun once called him “the David Beckham of science”), Nurse has also worked to explain science to a broad U.S. audience as a guest and co-host on The Charlie Rose Show.

Four years ago, his life took another unexpected turn. In the course of applying for a U.S. green card, which required obtaining the long form of his U.K. birth certificate, Nurse came to realize that the people he thought were his parents were his grandparents and that his much older “sister” had given birth to him out of wedlock at age 19. None of the three is alive, and Nurse does not know who his father was. He has willingly shared the poignant story with the public.

Nurse's current home, the leafy, gated campus of Rockefeller, feels like a serene oasis next to the chaos of Manhattan's streets. But Nurse proudly suggests that “anarchy” exists under the surface. He likes the university's lack of traditional academic departments, which he believes impede collaborations. He plans to bring this strategy to UKCMRI. “We're mixed up. And that's a little bit of what I'm trying to achieve in the other place,” Nurse says.

On a steamy summer afternoon last week, the same day his UKCMRI appointment was announced, the white-haired scientist, dressed casually in a white shirt and gray slacks, spoke with Science about his past, his recent suggestion to bolster U.K. funding for 100 to 150 top researchers, and his busy future. His remarks have been edited for clarity.

Q:Can you describe your vision for UKCMRI?

P.N.:One reason size is important is to take a multidisciplinary approach. Because it's large, it doesn't actually have to have a particular focus. If you set up an institute with 100 to 150 people working on stem cells or RNAi, the problem is, it often goes stale.

I've thought a lot about how to have an institute that will move with the times. About two-thirds of the 120 research groups will be at the junior end, in their 30s to early 40s. When they're developed, we will export them, help them find positions elsewhere. This is completely different from the usual philosophy in the U.S. where institutions try to hang on to people. It's a very supportive role for the whole national endeavor.

The second thing is that it won't be divided into academic departments and divisions. It's self-assembled from below. Individuals can belong to several interest groups and if their interests change, they can withdraw from one or join another.

Q:Can you clarify your recent comment about funding scientific elites?

P.N.:I think I was misunderstood. Some people thought I was going to kill all research funding for everybody except for 100 people, which is obviously stupid. All I was saying is that for the very best, we might want to think of supporting them in a nonbureaucratic way which gives them the maximum time for their creativity.

I was very much impressed by the way Howard Hughes [Medical Institute] does funding—I'm a Howard Hughes trustee—and I thought that would be a very interesting way of doing things not simply in biomedicine but in physical sciences, chemistry, maths. [Selected researchers] would be reviewed every 5, 6, 7 years, and if they're still highly productive, they get another 7-year tranche.

Most of these individuals are already getting research council funding and so on, and it's just a question of repackaging it in a different sort of way. It would be a couple of percent of the total funding of research. It could be administered by the Royal Society. This has got to be discussed. This is just me floating an idea.

Q:What are your thoughts about the possible U.K. science budget cuts?

P.N.:Two things. We have to tell the government that by cutting research today, they are in danger of burning the seed corn of the future. Because it's out of science that we will get the engine of wealth creation and improving health and improving the quality of life and our environment.

The second thing is that if they are going to reduce spending, they must always think about continuing to support the quality work. I wouldn't recommend them trying to second-guess the areas because usually committees don't do that well. What I would emphasize is supporting the highest quality people.

Q:What do you think of the push for more translational medicine research?

P.N.:When I was in the U.K., we used to think that everybody in the U.S. knew how to do translation. Now when I've come to the U.S., I find that everybody is worried themselves about how they do translation. I'm beginning to think that this is something nobody has really got on top of properly.

This is worth really looking at freshly, how to do things. This new institute will look at that. I'm going to start by focusing on the different cultures of the people involved. Because we have basic scientists, we have clinicians, we have the pharmaceutical industry. I'm by no means certain that we've worked hard enough on the sociology of that, to get that to work well.

Q:Why did you decide to share your birth story with the public?

P.N.:For my [birth] mother, actually. She had had to keep this secret for half a century because of the shame of it. And I felt by talking about it in public, it somehow in part compensates for that. It may sound a bit strange psychologically, but I'm saying, “No, this is OK, I'm talking about it publicly because it wasn't such a big shame.”

There's something ironical about being a really good geneticist and having my own genetics completely secret for so long. The irony almost appeals to me.

Q:What will you do with your lab?

P.N.:I will keep it for the next year or two then later will establish a lab in London. To keep a lab going is what keeps me sane and close to graduate students and postdocs. I never seem to do anything quite properly anymore because I'm juggling so much. But I sort of keep afloat. I wouldn't want to just run something without having my own scholarly activity. I sometimes think the people who just want to run things are not always the right people to run them.

9. Energy

# Dams for Patagonia

1. Gaia Vince*

Pressed by a demand for electricity, Chile is considering seven big dams and a transmission line through its southern wilderness; critics say the environmental risks have not been fully examined.

COYHAIQUE, CHILE—In rolling hills at the foot of a basalt massif, the people of this compact, ordered town live mainly by fishing and cattle ranching. For many, life is not dramatically different from that experienced by the pioneers who first cleared the valley nearly a century ago and built timber homes. But graffiti around town reveal a new disquiet. “Patagonia Sin Represas!” (“Patagonia Without Dams!”) is perhaps the politest of the slogans sprayed across the walls and buildings of this place, the capital of the Aysén region in Patagonia. They reflect anger over plans to build at least seven major hydropower dams in the area.

Home to condors and alpaca-like guanacos, puma, and blue whales, Patagonia is the tail end of the Americas, one of the last accessible nowhere lands on the planet. It contains the Southern Ice Field, the world's third most important reserve of freshwater after Antarctica and Greenland. And in its untamed wilderness of glaciers and mountain peaks, companies are preparing to raise not just hydrodams but also a 70-meter-high transmission line to transport power more than 2400 kilometers north to Santiago, Chile's capital, and the energy-hungry mines beyond. The line would require one of the world's biggest clearcuts, a 120-meter-wide corridor through ancient forests—fragmenting ecosystems—and the installation of more than 5000 transmission towers.

Proponents of the dams argue that hydroelectricity is a clean source of energy, that Chile needs the 3500 MW/yr of power to meet its development goals and, lacking oil or coal reserves, has no viable alternative (see sidebar, p. 384). But more than 50 international environmental groups have come together to try to block dam construction under the umbrella organization that uses the slogan “Patagonia Sin Represas” as its name.

“People feel strongly about these dams,” says Peter Hartmann, regional head of Chilean Friends of the Earth, one of the main opposition groups. “The megadam projects would change this region radically and ruin the valleys.” So unpopular are the construction schemes that Chile's second biggest bank, BBVA, announced in January that it would not be assisting the power company, HidroAysén, with loans for hydroprojects, citing environmental and social concerns.

The controversy raises questions about the goals of economic development and about the definition of environmentally clean energy—issues that divide the entire nation. National surveys show that about 53% to 57% of respondents are against the dams. This ensures that the government, which in the coming months is supposed to rule on the viability of initial projects, will face trouble no matter what it decides. Questions have been asked and answered by the thousands; still, key information is lacking.

## Unquiet land

In August 2008, HidroAysén, the company behind five of the proposed dams, submitted its environmental impact assessment (EIA) to Chile's national environmental authority CONAMA for regulatory approval. It is one of 32 government departments charged with assessing the EIA; reviewers found the document so wanting that CONAMA instructed the company to address more than 3000 comments and gave a 9-month extension.

In October 2009, HidroAysén submitted its response, a 5000-page document that brought more critical comments. These included criticisms that the EIA lacked data on seismic risks in an area known for earthquakes and volcanoes; gave no accounting of glacial lake outburst floods (GLOFs); and had insufficient information on impacts to key natural habitats, biosphere reserves of global importance, and wetlands and aquifers. The departments issued another 1000 comments in January 2010; HidroAysén's response—after another extension—is due in October.

According to Hartmann and his supporters, the EIAs submitted so far have overlooked entire areas of impact. “Many of the places to be assessed are inaccessible without a helicopter, so the assessors fly in, stay one night and see no wildlife and conclude there's nothing there. But that's no way to study an area,” Hartmann says. Among the diverse species threatened by the dams, he says, are endangered huemul deer (the Chilean national symbol), native fish otter, and unique cold-water corals that are only now being discovered by marine biologists at river outlets.

One of the three dam sites proposed by the company XSTRATA on the river Cuervo lies directly above the Liquiñe-Ofqui fault that runs northward from a triple junction where the Nazca, South American, and Antarctic plates meet. The plates move relatively slowly here, about 2 cm per year, compared with farther north near Concepción where the rate averages 10 cm per year, and the friction is less, says geologist Fabien Bourlon of the Research Center of Patagonian Ecosystems (CIEP) in Coyhaique. That means that the likelihood of a massive magnitude-8.8 earthquake, as occurred at Concepción in February, is less, but nevertheless, there is no study to support this, he adds.

Chile's National Geology and Minerals Service agrees, saying that proper seismic studies need to be carried out before a hydrodam is approved at the site. In 2007, 1 month after XSTRATA submitted its EIA declaring the Cuervo siting to be on a seismically inactive zone, the area experienced a massive earthquake that dislodged boulders into the fjord below, triggering a tidal wave that killed people on the opposite bank. “The government threw out their report,” Hartmann laughs.

“Actually, what we're seeing at the point where the three plates meet is an opening process—a rift—so volcanic or magmatic material could rise there,” Bourlon says. “And there's a volcanic gap at the dam sites. A line of volcanoes stops north of the site at Chaltén, and then there are none until Hudsen to the south. So it's likely there's an undiscovered volcano there,” he adds, maybe smack in between at Mount Arenales. “This area is very little studied because it's between two ice fields.”

Known volcanoes could be serious trouble for a dam, too, Bourlon says. If Hudsen were to erupt, large pieces of rock and debris could rupture the turbines, and volcanic ash could quickly silt it up. No one has looked at these risks, he adds. The transmission line for the project was originally planned to run right over Chaitén, the volcano that erupted so spectacularly in May 2008, with plumes of ash that rose 16,700 meters and buried the village. HidroAysén now plans to reroute the line, most probably via the coast.

XSTRATA points out that most of Chile is seismically or volcanically active, which has not prevented the country's numerous other hydroelectric projects from going ahead. “The Environmental Impact Study for Cuervo Hydroelectric Plant includes geological baseline studies with specific studies to establish the seismic and volcanological conditions and geological hazards in the project area,” says Christian Nuñez, environmental manager for Energía Austral, which runs the XSTRATA project. “To ensure the safety of the project, an engineering design was chosen that took into account the most extreme probable seismic scenario and the accelerations and landslides that could occur in this type of event. The Macá and Cay volcanoes, among others, have been incorporated into the risk evaluations,” Nuñez adds.

## Ice floods

The threat is not only from below ground. In Patagonia, glacial lakes often overrun their banks and send meltwater surging downstream; such GLOFs are becoming more frequent with global warming, according to the country's climate scientists. There are currently five GLOFs in the North Patagonian ice field, with a large one spilling at the headwaters of the Baker River since 2008.

“They are preparing to construct dams on what is probably the most unstable river system on the planet,” says Brian Reid, a limnologist at CIEP in the University of Austral, Valdivia. “To what extent it is active we don't know because it's never been studied.”

The GLOF analysis submitted in HidroAysén's EIA was “utter nonsense,” says Claudio Meier, a hydrological engineer at the University of Concepción. “They looked at water-level data for 1963 to 2007—less than 50 years—and extrapolated to obtain a 1-per-1000-year GLOF risk,” Meier says. “In fact, the peaks that they saw during the data period were just normal seasonal floods. The major GLOFs that occurred in that region were in 1962 and 2008; we've had six events there in the past 2 years.” The company needs to look at megaflood occurrences and come up with a risk for 1-in-5000-year and 1-in-10,000-year events, he says. GLOFs “have been much larger in the past than anything we're experiencing now” and have been known to flow at the extreme rate of 15,000 m3/s.

Reid also questions whether the dam could withstand the sediments a GLOF dumps, which both increase the flood levels and reduce the hydrodam's life span by raising the reservoir bed and clogging the turbines. “A GLOF in Iceland in 1996 deposited 1% of the world's sediment load for a year in a 12-hour period, making it the second largest river in the world during that time. Would the HidroAysén dam cope with this? Could they open the gates in time?” Reid asks. He doesn't think there is a clear answer, noting that “I am the only person who's even studied suspended sediments during a GLOF.”

HidroAysén says it is confident that its planned dam would withstand a GLOF, because it is designed to support a flow of 7000 m3/s. HidroAysén's experts—a range of in-house experts and contractors—calculate that a GLOF occurring during peak flow would double the rate to no more than 6000 m3/s, comfortably within the dam's margins.

## Breaking the wilderness

One of scientists' big worries is that hydrodams and other development could mar unique, unstudied areas. For example, on the Baker River, one of the proposed dams “would flood large areas of peat bog based on volcanic ash soils and destroy a lot of unique wetland habitat that hasn't even been studied,” Reid says. These areas are important habitats for fish and vulnerable to the practice of “hydropeaking,” flooding and draining a reservoir. “Artificial water level fluctuations disturb the natural seasonal synchronicity in a lake,” Meier says.

The effect of artificial daily pulses on fish can be devastating, says Evelyn Habit, a native fish biologist at the University of Concepción. “All the important spawning areas are in the wetland zone of daily flood and drop; if you lose spawning areas, you lose the species. Adults live in very deep layers and use the signal of water levels to know when to feed and reproduce, so if it's changing daily, it's unpredictable.”

The wetland areas are also an important source of fish food—terrestrial debris—that would be lost if the forests are disconnected from the water by artificial floods and dams. “All our fish are benthos feeders, and they need large, woody debris. There's no information on these impacts in the EIA,” Habit says. She's also concerned about how new roads and commercial development could affect unique fish species including, in the Yulton and Meullin lakes, the site of the proposed XSTRATA dam, a genetically distinct Galaxias platei species of primitive fish.

XSTRATA maintains that it has voluntarily set operating restrictions for its Cuervo plant to minimize the environmental damage from hydropeaking. “By maintaining variations within ranges that occur naturally in the existing banks, the company aims to limit the potential impact on the bank environment.” Nuñez says that simulations indicate that the hydropeaking variations “will be achieved with similar minimum and maximum levels to the current lake system.”

The Baker River is the most important river to protect, according to Habit, because of a historical quirk that has infused the system with uniquely rich biodiversity. During the last glacial period, 10,000 to 20,000 years ago, the river reversed direction, now flowing to the Pacific rather than the Atlantic. It contains “a unique population of fish that are endemic to Argentina,” such as a diplomystes of a primitive catfish genus and Odontesthes hatcheri (silverside), a type of atheriniform, Habit says: “It seems crazy to me to make such a big alteration to such pristine ecosystems.”

HidroAysén says it will replant trees elsewhere that are lost in its dam-building and “create an 11,560-hectare conservation area to safeguard the ecosystem and species.” XSTRATA is also planning what it describes as “one of the most ambitious programs of reforestation with native species in Chile's history,” to plant trees in parts of Patagonia that were burned by fires in the first half of the 20th century.

Nuñez, the company's environmental manager, also points out the greenhouse-gas benefits of hydro- versus fossil fuel–derived energy: “Energía Austral will have the capacity to displace from Chile's Central Interconnected System a total of 2.7 million tons of CO2/year.” HidroAysén has promised Patagonians an economic windfall if dams go forward: a reliable, cheap source of energy for the future.

Hartmann, standing under the three wind turbines that power the town of Coyhaique, says he's skeptical. “The same thing was promised for the people of Biobío before their dam was built; now they have the most expensive energy in the country,” he says. “This project is not something to benefit the people of Chile; it is to make a few private companies rich at the expense of our shared environment.”

And it is perhaps this more than anything that lies at the heart of the standoff. Those against the megadam projects do not feel that the cause to which they are being asked to sacrifice their shared environment is worth it. Most of the energy generated, they claim, will be used for privately owned mining concessions, which include Barrick Gold's environmentally controversial large new mine at Pascua-Llama, and not for Chilean households.

Thousands took to the streets of Chile's cities last month, from Coyhaique to Santiago, protesting the dams. Their numbers were swelled by those opposed to recent public attempts by HidroAysén to pressure the government into fast-tracking approval for the projects. The company's projected costs are now pegged at $7 billion. Thanks to another delay in the schedule requested by HidroAysén last month, the government will have until the end of the year to accept or reject the projects outright—or ask more questions. Many believe that the decision ultimately rests with the conservative billionaire president, Sebastián Piñera, who may be as personally divided as his electorate. He is both a conservationist and a supporter of large private-enterprise projects like these. If the dams get the go-ahead, electricity production could begin as early as 2015; if not, Chile will be one of the few developing countries to choose to protect its natural environment over short-term financial gain. 10. Energy # A Craving for Hydropower 1. Gaia Vince* Environmentalists and independent energy analysts argue that by improving efficiency and investing in renewable energy, Chile could find more than enough power within its borders for at least a decade—and without more dams. So far, however, energy planners have not been persuaded. The reason Chile must build at least seven new hydrodams, sponsors of the projects say, is that forecasts show that the country desperately needs more electricity—and that it must come from Chilean sources. Environmentalists and independent energy analysts have challenged this view; they argue that by improving efficiency and investing in renewable energy, Chile could find more than enough power within its borders for at least a decade—and without more dams. So far, however, energy planners have not been persuaded. To meet future energy demands, according to April 2008 government projections, Chile needs to double its installed energy-generating capacity over the next decade and triple it by 2025. With virtually no coal and no oil or gas, the country imports more than 95% of its fossil fuels. This is one reason Chile has the most expensive energy on the continent and why leaders want to expand domestic energy production. Half the country's electricity comes from plants fueled by Argentinean oil or gas and Columbian coal. The other half comes from existing hydropower schemes, many of them in the central zone around the Biobío River. In the summer of 2008–09, Argentina cut off gas supply to Chile at a time when months of drought had reduced Chile's hydropower capacity. The nation was plunged into blackouts. A powerful earthquake near Concepción in February again caused blackouts across the central grid after a single transmitter went down. Developing a new southern source of electricity became an attractive goal. “The earthquake definitely boosted our chances of approval. … We may have another year's delay, but we'll be approved,” predicts an employee of HidroAysén, the company proposing to build five of the dams, speaking on condition of anonymity. But a 2009 study by a consortium of Canadian and Chilean energy analysts disagrees. In their report, titled Are Dams Necessary in Patagonia?, Stephen Hall and his colleagues say that the country's projected electricity requirements to 2025 can be met by newly approved plans for coal plants. Even without the plants, they argue, Chile could obtain the 3500 megawatts per year promised from new Patagonian dams through energy-efficiency measures (3041 MW, they calculate) and renewable energy development (4383 MW). The total gain would be twice that generated from the Patagonian dams, they say. The green energy–conservation pitch has not persuaded Claudio Zaror, a chemical engineer at the University of Concepción and an energy adviser to the government. “Every year, the country needs an extra 500-MW capacity—another 8% a year,” Zaror says. “We have to get that energy from somewhere. Environmentally and economically, hydropower is our only feasible option.” The situation is more perilous than some realize, Zaror says, because droughts are predicted to become more frequent and more severe across the central region, which includes the Biobío River, source of most of the nation's hydropower. Studies by the Global Change Research Center in Santiago completed in May 2009 predicted that average rainfall would decline in this region by 15% from the present by 2050 and that by 2065 the flow of the Maipo River would drop 70%—from an average of 170 m3/s to 60 m3/s. These conditions have already arrived, thanks to a severe drought that began in 2008 and from which Chile has yet to recover. Already, Zaror says, the drier climate caused by an El Niña ocean-current shift is affecting the region between Concepción and Santiago. “During the 2008 drought, less than 15% of the baseload was met by hydro, and we had to import diesel for the power plants at$118 per barrel,” Zaror says. He argues that Patagonia won't be affected as severely by drought: With 92% of the country's glaciers retreating, he predicts, the south will continue to enjoy strong river flow.

For Zaror, the issue is clear-cut. “Per capita income correlates closely with per capita energy consumption, so for a developing country, consumption will rise,” Zaror says. “We have nearly 20% of the population living in extreme poverty at the moment. I want that number to decline, and we need energy for that.”

11. Profile: Nicholas Dodman

# Can Dogs Behaving Badly Suggest a New Way to Treat OCD?

1. Constance Holden and
2. John Travis
1. Constance Holden, a 40-year veteran of Science's News department, was killed in a traffic accident during preparation of this story, which was completed by John Travis. She is remembered by her colleagues and scientists at www.sciencemag.org/extra/holden/

One of the world's most popular vets argues that research on animals with behavioral problems can offer insight into people with obsessive-compulsive disorder.

NORTH GRAFTON, MASSACHUSETTS—Walking from his office to the nearby clinic, Nicholas Dodman sports the traditional white coat of a physician. But his orange tie covered with dogs is a hint that the patients he'll see later today aren't of the two-legged variety. Indeed, the 64-year-old veterinarian and founder of the Tufts University Animal Behavior Clinic is soon visiting with Baron, an 8-year-old brown Doberman pinscher who began compulsively licking himself after a sarcoma led to amputation of a hind leg.

Dobermans are an “oral breed, very licky, sucky, chewy,” Dodman says, and some will lick their flanks or limbs until raw and bleeding. Although the vet concludes that Baron isn't dangerously compulsive, he recommends, in addition to exercise and “environmental enrichment,” that the animal begin taking Prozac and memantine, a drug approved for the treatment of Alzheimer's disease symptoms in people. Next up for Dodman is Theo, a Bernese mountain dog who has suddenly become fearful around strangers; then Ginger, an overly aggressive Australian shepherd taking Prozac to help her behave; and Quincy, an anxious golden retriever who whimpers when his owner leaves the room. It's all in a day's work for the author of bestsellers such as Dogs Behaving Badly, The Dog Who Loved Too Much, and The Cat Who Cried for Help.

A fast, fluent talker with the charm of a good storyteller, Dodman regularly conducts seminars on pet behaviors for vets, animal trainers, and pet owners. He writes magazine columns; blogs for a dog Web site; runs another Web site on pets with his wife, also a veterinarian; and is a spokesperson for a spray that eliminates cat-litter odors. As such, it is perhaps easy to dismiss Dodman as the Oprah of the pet world.

But the veterinarian balances this celebrity with innovative animal research that appears in scientific journals. Earlier this year, for example, he and colleagues reported in Molecular Psychiatry that variations in the gene for a protein involved in central nervous system development may underlie “canine compulsive disorders” in Doberman pinschers.

Moreover, Dodman contends that animal compulsions bear relevance to human obsessive-compulsive disorders and that memantine may help people with OCD. A small clinical trial just completed supports his view, suggesting that the compound could be the first new OCD treatment in decades. Dodman even argues that studying aberrant animal behaviors may suggest treatments for a wide range of psychiatric conditions. Yet it hasn't been easy to convince other scientists. “Trying to get this concept over is like rolling a rock up a hill,” he laments.

Some researchers are now at least paying attention. Colleagues in nearby Boston have begun brain-imaging studies of his compulsive Dobermans. And Dennis Murphy, chief of clinical science at the National Institute of Mental Health (NIMH) in Bethesda, Maryland, is examining the Doberman-highlighted gene in people with OCD. The dog study “gives us a specific target to look at for compulsive behaviors in humans,” Murphy says. “This finding is too important to ignore.”

## The eureka moment

Dodman grew up in England, and an affinity for animals led him to train to become a vet. “I felt really strongly about animals being sentient beings and abhorred animal abuse. It just felt right at the time … to spend my days trying to help them as best I could,” he says.

Dodman's initial veterinary focus was surgery and anesthesiology. But after moving to the United States in 1981 to join the Tufts veterinary school, he struck up a friendship with Tufts pharmacology researcher Louis Shuster. Together, they became interested in developing treatments for horses exhibiting so-called stereotypic behaviors: repetitive, seemingly pointless actions such as pacing, cribbing, and wood-chewing. They hypothesized that the physical activity of these “stall vices” increased production of pleasurable endorphins, making the behaviors a form of equine self-medication. Dodman and Shuster found proof for their theory: Giving horses opioid antagonists, which block endorphin action, stopped the behaviors.

It was a “eureka moment,” says Dodman. “That one experiment is what turned me into a behaviorist.” It also led to a patent on treating equine stereotypic behavior with an opioid antagonist, the first of more than a dozen patents that Dodman, usually in concert with Shuster, has generated for Tufts.

Shuster and Dodman quickly began investigating treating stereotypic behaviors in other animals. Bull terriers often exhibit unnaturally obsessive “predatory” behavior, for example. They'll chase their tails or objects such as balls for long periods, compulsively carry and chew objects, and eat inedible material. Some cats hoard or compulsively lick their paws. Even birds may chronically pick their feathers, which, says Dodman, resembles trichotillomania, a condition in which people obsessively play with, and pull out, their hair.

Shuster and Dodman learned that besides blocking receptors for endorphins, opioid antagonists also block NMDA receptors, which mediate responses to the neurotransmitter glutamate. So they tried other glutamate receptor blockers, such as dextromethorphan—the cough medicine—and memantine, on compulsive behaviors in other animals. They found that combining memantine with fluoxetine, better known as the antidepressant Prozac, was effective in halting compulsive scratching behavior induced in mice. The Tufts team then tried memantine with or without fluoxetine on 11 dogs with various compulsive manifestations: tail-chasing, circling, snapping at invisible flies, and light/shadow chasing. Seven of the dogs improved.

About 7 years ago, Dodman and Shuster began talking with psychiatrist Michael Jenike, head of the Obsessive Compulsive Disorders Institute at McLean Hospital in Belmont, Massachusetts. OCD researchers had long focused on the neurotransmitter serotonin. Increasing serotonin levels with fluoxetine, a so-called selective serotonin reuptake inhibitor, can sometimes reduce symptoms of the disorder. But a subtle shift in thinking had begun developing among OCD investigators. In addition to the memantine animal work, studies of people had implicated glutamate signaling in OCD. A Yale University team, for example, had begun to test a drug that reduces glutamate release, riluzole, in people with OCD.

Given the lack of new treatments for OCD, Jenike tried memantine on a few of his patients and was impressed. He, Dodman, Shuster, and colleagues then launched a case-control study, comparing 22 people with OCD receiving standard treatment at the clinic with 22 similarly treated OCD patients who were also given memantine. The memantine takers, but not the controls, had a significant decrease in their OCD symptoms, the researchers reported in the February Journal of Clinical Psychopharmacology.

Jenike has now raised money to conduct a larger placebo-controlled trial of memantine. Despite all that, he remains skeptical that animal compulsions are directly analogous to OCD. “I have a hard time with the concept of a dog biting on his leg and calling it OCD. With OCD, you need to know what's going on in the head. It's kind of a big leap for me,” he says.

## Spontaneity is good

Researchers have traditionally sought to create animal models of mental health problems by, for example, genetically engineering or stressing rodents. Yet such models are viewed with caution. “Trying to create an animal model defined by behaviors which resemble human psychopathology is a tough one. … They capture, at best, only a fraction of the human syndrome,” notes Thomas Insel, director of NIMH.

Dodman contends that spontaneously occurring behavioral problems in animals offer a much more promising avenue of study than inducing a disorder does. “If I look at the DSM [psychiatry's Diagnostic and Statistical Manual], there's hardly a disorder in there that I don't see in animals,” he says. (Schizophrenia, he later acknowledges, is one of the exceptions.)

Dodman argues that there's a common theme to human OCD and compulsive animal behavior: instincts gone awry. “Human OCDs relate to hunting and gathering,” he asserts. Hoarding behavior, for example, is gathering run amok. Animal compulsions are similarly keyed to their basic instincts, according to Dodman. Grooming can go overboard, resulting in aberrant paw licking in cats and dogs and feather-pulling in birds.

Convinced that there's also a shared genetic component among people and animals for compulsive behavior, Dodman has been laying the foundation to confirm that theory for more than decade. In 2000, Dodman joined forces with geneticist Edward Ginns of the University of Massachusetts Medical School in Worcester, who was interested in screening select populations of people, such as the Amish, and animals, such as specific dog breeds and purebred horses, for disease genes. They collected hundreds of DNA samples from horses and dogs with severe compulsions and waited for technology to ripen. By 2007, the canine genome had been sequenced, and Dodman and Ginns, with the help of the Broad Institute in Cambridge, Massachusetts, began to probe the DNA samples of Dobermans with obsessive sucking or licking behavior. The search paid off at the end of last year when the team found that a variant of the gene for a protein called cadherin-2 (or neural cadherin) was over-represented in extremely compulsive Dobermans compared with normal ones.

Studies have suggested that cadherin-2 assists brain development, apparently helping neurons form synaptic connections. And Dodman believes the memantine and cadherin gene stories converge to further implicate glutamate in compulsive behaviors: Cadherins contribute to the formation and action of NMDA receptors, the target of memantine. Compulsive behavior “isn't all about the NMDA receptor, [but] it certainly isn't all about serotonin,” currently the prime target for OCD drugs, he says.

Dodman is now anxiously awaiting news from various collaborators. NIMH's Murphy should have results soon on whether the human version of the cadherin-2 gene or related cadherin genes are implicated in people with OCD. And Elaine Ostrander at the National Human Genome Research Institute in Bethesda is almost done with a genomewide survey of bull terriers who are severe tail chasers.

Dodman is particularly excited about the bull terrier study. Some members of this breed not only exhibit compulsive stereotypic movements but also are asocial and withdrawn, prone to seizures and “trances,” and display episodes of explosive aggression, all traits seen in autistic people. Dodman notes that a recent genetic study of people with autism has also implicated cadherins. “Things are getting curiouser and curiouser,” he says. That rock may be about to inch farther up the hill.