# News this Week

Science  16 Dec 2011:
Vol. 334, Issue 6062, pp. 1478
1. # Around the World

1 - Washington, D.C.
FDA Decision on Emergency Contraceptive Overruled
2 - Brasília
Controversial Changes to Forest Law Pass Brazilian Senate
3 - Durban, South Africa
Climate Negotiators Agree to Pursue New Treaty
4 - Beijing

## Beijing

### Merck Commits $1.5 Billion to Build in Beijing Merck has made the largest single research investment by a giant pharmaceutical company in China to date. The New Jersey-based firm, known as MSD outside the United States, last week said it plans to spend$1.5 billion over the next 5 years on R&D, under the direction of a pioneer staff of 260 now in rented offices in Beijing.

Zhang Ming-Qiang, vice president and head of MSD R&D Asia, says Merck anticipates that China's pharma market—currently second in the world—will become the world's largest in 10 to 15 years. Two significant challenges lie ahead, according to Zhang. First, China has many talented young researchers, but is short on scientists experienced in drug R&D who can serve as mentors. Second, China's regulatory landscape is unclear, and companies often have trouble discerning a clear process to follow when they apply for new drug registration.

Merck previously established a commercial headquarters in Shanghai and manufacturing facilities in other parts of China. The first phase of construction is expected to be completed in 2014; it will house about “600 employees working in the areas of drug discovery, translational research, clinical development, regulatory affairs and external scientific research programs,” according to a company announcement.

## London

### Courtroom Neuroscience Not Ready for Prime Time

Using brain scanners to determine whether a witness is lying is premature and unrealistic, notes a 13 December report by the Royal Society. However, the report's authors say, brain scientists might eventually be able to help answer other legal questions, such as whether a violent offender is likely to strike again and at what age children's brains are developed sufficiently that they should be tried as adults; the report suggests that the United Kingdom's current cutoff, 10, is too low.

At best, functional magnetic resonance imaging might be able to detect deliberate lies, but not if a witness believed he was telling the truth, said experimental psychologist Nicholas Mackintosh of the University of Cambridge, who headed the Royal Society's working group on neuroscience and the law, at a press briefing 9 December.

Still, neuroscience can potentially provide “hard evidence” in other areas, Mackintosh said, such as identifying the presence of a gene that codes for monoamine oxidase, which is present in many violent criminals who were abused as children, and could signal an increased risk of recidivism. Researchers are also studying whether brain scans could one day be used to determine if a person is actually experiencing pain or is malingering to obtain government benefits. http://scim.ag/courtneuro

## Atacama Desert, Chile

### Big Step for Extremely Large Telescope

What will be the largest optical-infrared telescope ever built took a big step forward on 9 December. The European Southern Observatory (ESO) gave the green light to start bulldozing roads on the site of the European Extremely Large Telescope (E-ELT), to be erected at Cerro Armazones in northern Chile. Engineers will also begin developing the instrument's adaptive optics.

“The E-ELT is starting to become reality,” ESO Director General Tim de Zeeuw said in a statement. The move did not represent full approval for the €1.1 billion behemoth, however, because some of ESO's 15 member states have not yet secured needed funding.

Still, planners expect construction to begin in 2012 and observations to start in 2022. When finished, the E-ELT will have a main mirror 39.2 meters across, dwarfing today's largest telescope, the Large Binocular Telescope, which is equivalent to an 11.9-meter instrument. Meanwhile, two rival telescope efforts in the United States—the Giant Magellan Telescope and the Thirty Meter Telescope—are struggling to secure funding. http://scim.ag/E-ELT

2. # Random Sample

## Cannibalism on Ice

Inuit hunters in Greenland and Canada have long known that polar bears—usually adult males—might kill younger polar bears for food. But until this August 2008 photograph was taken, such events had been reported only on land, not on sea ice, and no one had photographed it before. In the December issue of Arctic, photographer Jenny Ross and arctic biologist Ian Stirling of Environment Canada in Edmonton note that there have now been three documented sightings of adult male polar bears on sea ice feeding on younger bear kills. They suggest that given the dwindling sea ice and the scarcity of seals nearby at that time of year, young polar bears may simply be the most available prey. But, they add, it might also be a sign of things to come: A warming climate and less and less sea ice will send seals northward even earlier in the summer, and the frequency of intraspecies predation could increase.

## Grand Canyon Too Crowded? Blame Climate Change

Climate change has altered the timing of plants blooming, insects hatching, and birds migrating—and it may be altering human vacation plans. A team analyzing attendance data at U.S. national parks from 1979 through 2008 found that of nine national parks showing increases in their average spring temperatures, seven also showed that peak tourist attendance occurred earlier in the season, by an average of 4 days. At Grand Canyon National Park, for example, peak attendance shifted from 4 July in 1979 to 24 June in 2008, the researchers report in an upcoming issue of International Journal of Biometeorology. Of 18 national parks that didn't experience climate change, only three showed shifts in peak attendance. Other major factors likely to influence park visitations—including population growth, economic trends, and travel costs—would tend to affect the total number of park visits but not their timing within the year, the researchers say.

## Tracking Contaminants in Whales—Using Their Earwax

Hold the giant Q-tip: The waxy buildup in a whale's ears may contain interesting data about its exposure to contaminants. A wall of blubber and muscle protects whales' ears from seawater, sealing the wax inside. The wax plugs are made up of laminated layers that can be matched roughly to a whale's age, like tree rings—and those layers can also be the repository of chemicals from the surrounding ocean.

Graduate student Eleanor Robinson, with environmental scientist Sascha Usenko and biologist Stephen Trumble, all at Baylor University in Texas, have worked out an analytical method to quantify the compounds sequestered in each wax layer. They use earplugs taken from dead whales (the earwax harvesting must be done posthumously, because marine mammals are protected by U.S. law).

Last month at the North American meeting of the Society of Environmental Toxicology and Chemistry in Boston, Robinson reported the team's first data, from an earwax plug from a whale that died in 1969 along the California coast; the plug ended up in the Smithsonian Institution's collection. The 6-centimeter-long earplug included a decade's worth of data and yielded small amounts of the pesticide chlordane, banned in the United States in 1988, as well as PCBs. The concentrations of chlordane decreased over the years, whereas the levels of PCBs remained relatively steady throughout the whale's life.

Unfortunately, the analytical method destroys the sample, Robinson says. And although the team may eventually be able to extrapolate earwax data to a whale's total “body burden” of chemical contaminants, determining when and where the animal picked those contaminants up, and whether they affected its health, will be an entirely different ball of wax.

## By the Numbers

655,000 — Estimated number of worldwide malaria deaths in 2010, a 5% reduction over 2009, according to the World Health Organization's World Malaria Report issued this week.

10% — The amount by which Cancer Research UK will cut its annual £330 million research budget over each of the next 3 years in response to declining donations.

$388,375 — Amount paid at an auction for the Apollo 13 checklist of commander James Lovell, which includes his handwritten calculations. It's the second most expensive space item on record, after a$2.9 million Vostok 3KA spacecraft sold last April.

3. # Newsmakers

## New Chief for HHS's Research Misconduct Office

David E. Wright, a science historian at Michigan State University (MSU) in East Lansing, will soon lead U.S. government efforts to guard against misdeeds in biomedical research. The Department of Health and Human Services (HHS) announced last week that Wright will become chief of its Office of Research Integrity (ORI) in January.

Wright, 66, now chairs MSU's department of community, agriculture, recreation, and resource studies. He served as MSU's research integrity officer from 1993–2004 and he has consulted for ORI since 2001. That led to his interest in leading ORI: “I have done it [research integrity] at the institutional level and consulted with the feds. I have a great deal of respect for the work [ORI] does,” Wright says.

ORI has lacked a permanent director since September 2009, when former director Chris Pascal retired after 13 years. http://scim.ag/HHSORI

4. Infectious Disease

# Taking a New Shot At a TB Vaccine

1. Kai Kupferschmidt*

Eager to replace the current tuberculosis vaccine, scientists hope to push a slew of promising candidates through clinical trials—if the money can be found.

When Barry Bloom, a veteran of tuberculosis research, wants to illustrate how far he and other scientists have gotten fighting the disease, the Harvard University immunologist shows a picture of a man holding a small saw in front of a huge redwood tree. The photograph usually gets a laugh out of the audience, but it illustrates a public health challenge that is far from funny: About one-third of the world's population is infected with the pathogen Mycobacterium tuberculosis. And although the bacterium is dormant in most of those people, they have a lifetime chance of 1 in 10 that the pathogen will wake up and cause tuberculosis.

Antibiotics can usually stop an active TB infection, but the needed drugs are too costly for many developing countries, and compliance is a problem because they need to be taken for months. The pathogen is also becoming increasingly antibiotic-resistant, requiring ever-more-expensive cocktails of drugs. And even though the World Health Organization reported this year that the number of TB cases is going down, the disease still kills 4000 people every day.

For many people around the globe, there's only one line of defense against the bacterium: a shot of a 90-year-old problematic vaccine that they get shortly after birth. That could soon change. “Ten years ago, not a single tuberculosis vaccine was in clinical development. Now there are a dozen,” says Stefan Kaufmann, an immunologist at the Max Planck Institute for Infection Biology in Berlin.

The emergence and rapid spread of multidrug-resistant strains of M. tuberculosis and the United Nations's declaration of halving TB deaths by 2015 as a Millennium Development Goal have led to an influx of private and public money, with product-development partnerships such as the Aeras Global TB Vaccine Foundation and independent nonprofit foundations such as the Europe-based Tuberculosis Vaccine Initiative (TBVI) leading the way. Now, after years of lab work and initial safety testing in humans, the most advanced of these candidates are entering their first human efficacy trials. “This is a real turning point,” says Jelle Thole, director of TBVI.

But with this new hope come challenges. Researchers are wrestling with how to select the best candidates to advance to much larger trials—and they are wondering how to pay for those final rounds of testing. Nor are there any guarantees of success at the end of this road. A human trial of one new tuberculosis vaccine was halted at the end of September because of apparent side effects.

## Out with the old, in with the new

The only currently available TB vaccine was developed between 1906 and 1919 by French scientists Albert Calmette and Camille Guérin. They cultured M. bovis, a relative of M. tuberculosis that mainly infects cows, for so long that it lost numerous genes and with them its virulence. The weakened, or attenuated, strain, dubbed Bacillus Calmette-Guérin (BCG), would become the world's most widely used vaccine. It has been given more than 4 billion times, and although there's no definitive evidence that it can actually prevent an initial infection, the vaccine can help the body limit the growth of the mycobacteria enough to protect many children from developing severe forms of tuberculosis. “It saves up to 60,000 lives every year,” says Willem Hanekom of the University of Cape Town in South Africa.

But a childhood BCG shot does not protect adults or adolescents against pulmonary tuberculosis, the most prevalent form of the disease nowadays. For unknown reasons, the vaccine also seems to work better for children in some places than in others.

More troubling, there is no evidence that the vaccine prevents tuberculosis in children already infected with HIV, and the vaccine itself is unsafe for many. An estimated 1% of these children cannot control the vaccine bacterium and develop disseminated BCG disease. Many of them die. “If it were proposed for use today, no one would allow such a vaccine to be used in an HIV-endemic country,” Bloom says. “But it does prevent meningitis and disseminated tuberculosis in healthy children, so no one wants to pull it out.”

To build a new vaccine that is at least safer, if not actually better at preventing disease, than BCG, researchers are pursuing numerous strategies: adding certain genes to BCG, taking specific genes out of natural, unattenuated mycobacteria, expressing M. tuberculosis genes in viruses, or combining proteins from the pathogen with new adjuvants. In general, the first generation of candidates can be divided into those intended to directly replace BCG as an infant vaccine or those intended as a booster of BCG. But researchers are also examining “vaccines” that could help people with dormant TB infections by stimulating the immune system to flush out mycobacteria.

The first replacement candidate to show substantially greater protection than BCG in various animal models was rBCG30, developed at the University of California, Los Angeles. The vaccine is a BCG strain overexpressing the M. tuberculosis protein Ag85A, believed to be important for stimulating a strong immune reaction to the bacterium. A phase I clinical trial, completed last year in the United States, suggested it was safe.

Another potential replacement is VPM1002, a new BCG strain developed at Kaufmann's lab. The scientists took BCG and added the gene for a protein called listeriolysin from the bacterium Listeria monocytogenes. Making this enzyme enables the proteins from the bacteria, which an infected cell normally traps inside a special compartment, to escape into the cytosol—boosting the vaccine's ability to rouse the immune system. In early animal tests, the new strain showed better protection than BCG. A phase II trial to establish safety and dosing in infants started 3 weeks ago.

A third replacement candidate, Aeras-422, employs a similar strategy, but it has run into trouble. The vaccine is a BCG strain genetically modified to overexpress three proteins and to make perfringolysin, an enzyme from yet another bacterium, so that it, like VPM1002, perforates the cell's encapsulating membrane and spills BCG proteins into the cytosol. But administration of this vaccine to people has recently been halted because of safety concerns that arose in a phase I trial in the United States: Two vaccinated people developed shingles, a painful skin rash caused by reactivation of a dormant virus.

Many scientists see perfringolysin as the most likely culprit, but Aeras is still investigating. “There is no obvious explanation at the moment,” Kaufmann says. “We hope that Aeras will follow this up to see whether there is a more general mechanism at work.” But there are no data to indicate that VPM1002 has similar problems. Unlike perfringolysin, listeriolysin is rapidly degraded in the cell and is not cytotoxic. “The safety of VPM1002 has already been assessed in clinical trials in Germany and South Africa without any problems,” Kaufmann says.

Some of the proposed booster vaccines are a combination of specific M. tuberculosis proteins, which on their own don't generate disease symptoms, and adjuvants. The two booster candidates that have advanced furthest use a different strategy: equipping harmless viruses with genes for mycobacterial proteins so that they can infect cells and produce the proteins, stimulating an immune response against the pathogen. Crucell Ad35/Aeras-402, for example, is an adenovirus producing three proteins naturally made by the TB bacterium: Ag85A, Ag85B, and TB10.4, a protein that is not present in BCG. The vaccine is currently being tested for efficacy in clinical trials in HIV-positive adults and infants. And MVA85A, developed at the University of Oxford, is a modified vaccinia virus that has been engineered to express Ag85A. It is currently being test ed in two phase IIb proof-of-concept trials in South Africa and Senegal in 2784 infants and in 1400 HIV-infected adults.

Initial data from the infant MVA85A trial are expected next year. This will be the first time efficacy data on one of the new vaccine candidates become available—and a pivotal moment, Kaufmann says: “If the first efficacy data is positive, it will push the whole field ahead, but if it is negative, it could make funding our efforts even more difficult.”

The MVA85A study is designed to detect whether the vaccine boosts BCG's normal protection rate by 60%. If that goal is achieved, the next step would be a phase III trial, the last step before a vaccine could be put on the market. And that is where money becomes a major issue.

## Whittling down the field

Results from the phase II trials of various other vaccine candidates will begin to trickle out later next year, potentially forcing hard decisions. A lot of money has been poured into tuberculosis research recently from sources such as the U.S. National Institutes of Health, the European Commission, the Bill & Melinda Gates Foundation, and the Wellcome Trust. Kaufmann estimates that about half a billion dollars is available every year for tuberculosis research, about a fourth of which goes into vaccine research and development.

But vaccine developers fear that there won't be enough to launch the critical, large phase III clinical trials, especially if multiple candidates need to be evaluated. Whereas a phase I vaccine trial costs between $1 million and$5 million, and a phase II trial, between $5 million and$20 million, up to $200 million is needed for a phase III trial. “The field needs more money,” says Kaufmann, who estimates that$1 billion a year is needed for the next 10 years to fund TB vaccine research and development.

TBVI is among those trying to raise that money. At a recent meeting in Madrid, its officials unveiled an ambitious plan to finance numerous vaccine trials, including two phase III trials, with the aim of having two TB vaccines on the market in 2020. TBVI's Thole estimates that the organization would need $750 million over the next 10 years to pull that off. The initiative is seeking money from the European Investment Bank, with European governments supporting the “loans” with guarantees. “That money is an investment that will be paid back by revenue from the royalties paid on the two successful vaccines,” says Thole, who contends that several governments have already shown interest in the plan. Aeras, a U.S.-based nonprofit organization that was founded in 2003 to develop a TB vaccine, is taking a slightly different route: “We think commercial partners are crucial,” says Thomas Evans, chief scientific officer of Aeras. Any phase III vaccine trial of its candidates would likely be funded by a consortium that included the pharmaceutical industry, he notes. “What TBVI is doing is very innovative, and we are supportive of them going ahead with this because more money is badly needed,” Evans says. “But they will have to deal with the issue of getting the pharmaceutical industry on board while also needing to recoup the money.” Everybody in the field agrees that there won't be enough money for all of the vaccine candidates to move into phase III trials. Aeras alone is supporting six TB candidates in phase I or II clinical trials. And there are another six vaccines backed by other sponsors and many more pushing into clinical trials. So the big issue now is to identify those vaccines that are most likely to succeed. “It is ironic,” Kaufmann says. “We used to have no candidates; now we have too many.” To address that problem, scientists from Aeras and TBVI are working to establish clear criteria for choosing the most promising candidates that should advance to the next stage of clinical testing. Their blueprint is due out next spring. Overall, there's a lack of tools to evaluate potential tuberculosis vaccines in both animal studies and human trials. It is unclear, for example, how well the animal models predict the effectiveness of a vaccine in people. “We are looking for a vaccine that works where BCG does not, but our animal models are designed to show where BCG works,” Ann Rawkins, an expert on animal models of tuberculosis at the Health Protection Agency in Porton Down, U.K., said at the conference in Madrid. For those candidates ready for advanced clinical trials, other questions loom large. What populations should be tested, for example? At the moment, phase I and II TB vaccine trials are performed mostly in infants and HIV-positive adults. Because these groups develop tuberculosis more often, fewer subjects are needed to see a significant effect of the vaccine. “But even in areas with high prevalence of HIV, it is the HIV-negative adults who are most likely to transmit TB,” says Hanekom, who contends that these people should be the first to be studied in clinical trials. “Otherwise, there is a possibility that a negative trial in HIV-positive adults may compromise development of a candidate that might work in HIV-uninfected persons.” To help evaluate all the TB vaccine candidates, some researchers have begun grappling with the idea of so-called challenge trials. For malaria and cholera, scientists have the option of deliberately infecting volunteers with the relevant pathogen to see whether a vaccine works, because both diseases can be readily treated. These challenge trials can save a lot of time and money, but researchers agree that directly infecting humans with the TB bacterium would be unethical because treatment currently requires a 6-month regimen with three or four antibiotics, and there is a risk of not eradicating the pathogen entirely. Yet Helen McShane has proposed challenge trials in which people would receive a candidate TB vaccine before being injected with BCG, the current vaccine but also a live, replicating mycobacterium. She argues that if the candidate, for example, helps the body more quickly eliminate BCG, it should also protect against TB. But others are skeptical. “We would only find out whether we are protecting against the current TB vaccine and not against the real pathogen,” Kaufmann says. “We are in the very early days, but a challenge model would be game-changing in some ways, so we need to find out whether it is possible to get a challenge model,” Evans says. ## Looking ahead Even if scientists surmount all these difficulties and deliver a new vaccine by 2020, the fight against tuberculosis would be far from over. “This is just the first generation of candidates, and they are all far from perfect,” Kaufmann says. They are, with respect to Bloom's redwood picture, just a slightly bigger saw. A different tool that may one day be wielded is a tuberculosis vaccine designed to eliminate or better control dormant infections; even the current, rigorous antibiotic regimen often leaves some mycobacteria untouched. Just 2 weeks ago, Aeras announced the first phase I clinical trial of a vaccine, SSI H56-IC31, specifically intended to target those dormant bacteria. Developed at the Statens Serum Institut in Copenhagen, the vaccine consists of an adjuvant and recombinant versions of proteins known to be made more often by dormant forms of the TB bacterium. All these candidate vaccines have scientists reconsidering whether it's realistic to develop an ultimate vaccine that truly stops M. tuberculosis from ever initially establishing an infection in a person. At first, Evans says, “the feeling was that bar is too high; let us try to prevent disease first. But we need to start looking at vaccine candidates now that could prevent infection.” That could be the tool that finally fells Bloom's colossal tree. • * Kai Kupferschmidt is a science writer in Berlin. 5. Traditional Medicine # Piercing the Veil of Ayurveda 1. Pallava Bagla Enthusiasts hope that clinical trials of Ayurvedic medicines will buff the ancient art's tarnished reputation. BANGALORE, INDIA—At a gleaming new facility here in India's biomedical research hub, chemists and Ayurvedic practitioners are teaming up to breathe new life—and instill scientific rigor—into an ancient art of healing. At the$10 million Institute of Ayurveda and Integrative Medicine (IAIM), several dozen researchers scour ancient manuscripts for therapeutic recipes, cultivate rare medicinal plants, and attempt to isolate active compounds. Meanwhile, healers use modern diagnostics to refine treatments at IAIM's 100-bed hospital.

The new institute is part of a concerted effort to buff Ayurveda's reputation. Last May, the European Union, concerned about mercury and other heavy metals in preparations, banned the sale of nonauthorized Ayurvedic products. Since then, no preparations have passed muster. Even in India, where Ayurvedic medicine has been practiced for 3500 years, “today most people turn to Ayurveda literally as a last resort,” says Vaidya Balendu Prakash, director of the VCPC Research Foundation, an Ayurvedic treatment center in Dehradun.

Hoping to turn the tide, India's Council for Scientific and Industrial Research (CSIR) in New Delhi has embarked on a $25 million initiative to modernize a discipline practiced by 500,000 registered healers in India alone. The initiative will subject concoctions—from benign herbs to bona fide poisons—to modern analysis. Proponents face an uphill struggle. “Ayurveda has been demonized by modern science,” says Rajiv Kumar, a chemist at Tata Chemicals Innovation Centre in Pune. Kumar lays the blame on healers, who he says are “closed and secretive about what and how they practice.” Healers say that secrecy is necessary to protect intellectual property. They aim to balance three “energies” that roughly correlate to vata, or wind; pitta, or bile; and kapha, or phlegm. According to ancient texts, all doshas, or ailments, arise when the energies are off kilter. Putting Ayurvedic medicine on a firmer scientific footing won't be easy, as Prakash attests. A second-generation healer, he is promoting a silver- and mercury-based treatment called “Navjeevan” that he has refined for acute promyelocytic leukemia. At the U.S. National Institutes of Health in Bethesda, Maryland, in June 2010, Prakash presented positive results from his Dehradun lab and from others on Ayurvedic anticancer treatments. But he acknowledges that some data were ambiguous; few in the audience were swayed. To tamp down toxicity concerns, Prakash invited Kumar to vet Navjeevan in 2005. Kumar was astonished. “It's scary to see how callously mercury is handled by the pharmacists” in the preparation of some medicines, he says. But to his surprise, Kumar found that Navjeevan's months-long preparation had converted liquid mercury to a complex or polysulfide form of mercury, blunting its toxicity, he says. The faith that healers place in poisons has tended to undermine Ayurveda's reputation. The field took a hit in August 2008, when Robert Saper of Boston Medical Center and colleagues reported that one-fifth of 193 Ayurvedic medicines they tested after purchase over the Internet contained detectable levels of lead, mercury, or arsenic. Writing in The Journal of the American Medical Association, the researchers called for “strictly enforced, government-mandated daily dose limits for toxic metals in all dietary supplements.” “This led to a severe backlash and growing distrust in Ayurveda,” says IAIM founder Darshan Shankar. Some experts are dubious that Ayurveda can navigate the path to respectability offered by standard clinical trials. “The use of controls and placebos, so central to clinical trials, sits ill with Ayurveda,” says Marthanda Varma Sankaran Valiathan, a cardiac surgeon and former vice chancellor of Manipal University. Ayurveda, he explains, “regards every individual as unique and the package of therapeutic measures, including virtuous conduct, lifestyle, diet, and drugs, as inseparable.” Others argue that Ayurveda's relevance will fade if concoctions don't pass standard tests. One formulation used to treat rheumatoid arthritis did well in a double-blind, randomized match-up against a Western drug. In the first trial of this kind involving a total of 43 patients, people were assigned the unnamed Ayurvedic preparation, the Western drug methotrexate, both, or a placebo. “All three treatments were equivalent in efficacy, but adverse events were fewer in patients treated with the Ayurvedic medicine,” a team led by Daniel Furst of the University of California, Los Angeles, reported in the June issue of the Journal of Clinical Rheumatology. “This marriage of a traditional medicine system with modern inquiry augurs well and is probably the best way forward,” says microbiologist Padma Venkat, IAIM director. Ayurveda may soon make its debut in Western apothecaries. A herbal preparation mentioned in Ayurvedic texts and extracted from the weedy Mexican poppy (Argemone mexicana) led to the discovery of a possible treatment for psoriasis, a skin disorder that afflicts 2% of people around the world. Desoris, developed by Lupin Laboratories in Mumbai, is now in clinical trials. And last year, following leads from Ayurveda, CSIR researchers discovered what they claim is a memory-enhancing compound derived from brahmi (Bacopa monnieri), a marsh plant in northern India. To Venkat, the findings herald the emergence of a new discipline: Ayur-biology. But restoring the ancient art's reputation, she acknowledges, will not happen overnight. 6. U.S. Science Policy # Suresh Expects Low-Cost Ideas Will Mean a Big Payoff for NSF 1. Jeffrey Mervis The director of the National Science Foundation has hit the ground running with a flurry of new programs aimed at leveraging precious federal dollars. One year into his 6-year term as director of the National Science Foundation (NSF), Subra Suresh is pushing the 60-year-old basic research agency in new directions. The most visible evidence is a quartet of new initiatives intended to promote entrepreneurship, accelerate the review process, foster international collaborations, and improve conditions for women. The soft-spoken former Massachusetts Institute of Technology dean of engineering says he's simply trying to get more out of NSF's$6.8 billion budget. But his modesty hides a keen political sensibility.

It's no accident that each of the initiatives meshes with one of the Obama Administration's priorities for bolstering U.S. science, and none requires a big investment. That latter feature is especially pleasing to congressional appropriators as they struggle to keep agencies healthy while trimming overall federal spending. In fact, NSF's reputation for sound fiscal stewardship helped it obtain a 2.5% budget increase in 2012, a rare boost in the current era of austerity (Science, 25 November, p. 1041).

The new Innovation Corps (I-Corps) program, for example, reflects that combination of frugality and fresh thinking. The frist round awarded $50,000 to 21 scientists to test the waters for a product based on their NSF-funded research. The new wrinkle is that the scientists are teamed with an experienced entrepreneur and a graduate student, and each trio gets a 3-month crash course to square their idea with what potential customers want before seeking funding from venture capitalists or a government-funded program for start-ups. “I picked it because we could do it without a lot of extra dollars,” Suresh says. “And I knew that the issue resonated with Congress and the Administration, and with industry and the community.” A second initiative, Science Across Virtual Institutes (SAVI), leverages something NSF is already doing—helping U.S. scientists collaborate with their peers abroad—by attracting even larger investments from other countries. By requiring buy-in from not only the discipline-based program but also NSF's international office, SAVI also advances Suresh's goal of One NSF, a management concept aimed at breaking down some of the walls between NSF's seven discipline-based directorates and two offices. It's not that Suresh doesn't think about money. He faces the chronic problem of balancing support for individual researchers against the need for expensive new facilities used by an entire discipline. NSF's decision to pull out of the proposed Deep Underground Science and Engineering Laboratory in South Dakota (Science, 17 December 2010, p. 1596) will relieve some of the immediate budget pressure, but the community's ravenous appetite for new infrastructure will test Suresh's management skills. Suresh is also looking inward. One major effort involves fine-tuning NSF's vaunted merit-review system; the challenge will be to prevent success rates on applications from dipping too low in an era of flat or declining budgets. This week, NSF's oversight body, the National Science Board (NSB), may adopt a new definition of its controversial second criterion for assessing grant proposals, relating to the broader impacts of the research apart from its scientific merit (Science, 14 October, p. 169). An internal working group is also reviewing every aspect of NSF merit review. The timing is not coincidental: In May, Suresh will chair an international summit on merit review hosted by the U.S. government. A global perspective comes easily to the Indian-born Suresh. But as a naturalized U.S. citizen, he's thoroughly American when he comes to assessing the likelihood of China surpassing the United States in his lifetime (he's 55). “Well, it's clear that they are increasing their investment in infrastructure,” he says. “But I also believe in the nimbleness and resilience of the American enterprise. So I'm not willing to concede that we will lose our scientific preeminence and become number 2 or number 3 [in the world]. The competition has never been as severe as we face now. But it may still not be too late to stay on top.” On 7 December, Science sat down with Suresh in his Arlington, Virginia, office to talk about these and other issues. Here are excerpts from that interview. Q:Why did you launch the Innovation Corps initiative? S.S.:Our mission is basic research, and that's not going to change. But how do we take that basic research output and get the biggest bang for the buck without diverting precious basic research dollars? There are many models for that. I-Corps tries to make use of NSF's reach, scope, and statute, and also bring in private partnerships. … The idea is to do something new, leverage something significant, and also improve our internal processes. If we want to give an award for 6 months, it doesn't make any sense to have a review process that takes 9 months. So we wanted to accelerate that review process. And that's exactly what we did in the first round of awards. We made them 4 weeks after the solicitation. Q:What do you hope SAVI will accomplish? S.S.:SAVI has a couple of objectives. In the spirit of One NSF, how do we make sure that people can work better together? For example, in mathematics we have an NSF-funded center at Brown University and three institutions in North Carolina, and we got them together and collectively they began to think of international partners. But here's the thing. A program director can do some things, but if NSF as a whole does something, our leveraging power is significantly higher. So we set up a common policy for all SAVI activities. It has to be supported by the program and division director and have the endorsement of the assistant director and the international office. And that's not just, “Yes, it's a good idea. Go do it.” It also has to come with dollars. And that's a real endorsement. Brown and the North Carolina institutions decided they wanted to work with a group of Indian institutions. So NSF put up$6 million, and the Indian government put up \$20 million. That's real leverage. Now we deal directly with the secretary for science and technology for India, and that gives us tremendous leveraging power.

Q:How do you feel when elected officials and candidates deny the scientific evidence for climate change caused by increasing CO2 levels from human activity?

S.S.:Well, my reaction is, there should be room for different interpretations and disagreements. But facts are facts. NSF doesn't do any internal research. We support research through a transparent and open process. Let the scientists publish and let people interpret, some one way and some another way. And my belief is that, in the end, whatever is the truth will prevail.

Q:NSF managed to boost success rates by using most of its stimulus money to fund proposals already in the pipeline. Can you sustain current success rates with the 2012 budget?

S.S.:The success rate depends on a lot of factors. It's not just the number of proposals and the dollars available. It also depends on how we process the proposals, including how many times the same idea gets resubmitted. If an idea has no chance of getting through the process, does it make sense to have it be reviewed over and over again?

Within NSF, the success rates for particular programs vary by a factor of 4. So another question is whether we are setting up the right expectations for the community. … It's also field-specific. There may not be one magic solution for all of NSF.

Q:Some people have suggested that NSF should require universities to show evidence of their success in broadening participation—one of the criteria under the “broader impacts” of a research activity—as a condition for continued funding. Is that an appropriate role for NSF?

S.S.:One thing the NSB task force on broader impacts has looked at closely is metrics for success. And these are inherently long term. The time frame in which you assess the impact is much longer than the duration of the grant itself. That makes it much harder to say, at the end of 3 years, whether you've had an impact or not. So one thing we've been grappling with is how to put quantifiable, verifiable, and accessible metrics into everything we do, including broader impacts.

Q:Is having a separate account still the best way to fund new large facilities?

S.S.:We now have an MREFC account. If all the costs come out of [research], it will be a completely different discussion. So one of the in-between things we are trying to do is to look at a longer time horizon. We also are looking at different [budget] scenarios. One is reasonably optimistic, one is flat, and one is highly pessimistic. And then we're asking the question: What is the minimum level at which we can do [a particular project]? And is that good enough? Is it worth it? And if the answer is no, then it falls off the list. …

We're looking at a number of criteria. What's the overall value of the science? How large is the community that will be impacted? How much money has already been spent? It's project-based, and it's not just 1 year. If we fund fewer projects this year and do more next year, it may seem like a convenient solution to an immediate budget crunch. But you may end up wasting money in the long run because costs will go up. …

The flexibility that Congress has given us [to shift money from other NSF accounts] is good. But it also eats into basic research. It's a fine line to walk. If you have a separate account for facilities, as we do now, then sometimes you don't realize the cost impact. In a zero-sum game, it's not coming out of someone else's pocket. It's coming out of our pocket.

Q:Why did NSF pull out of the proposed Deep Underground Science and Engineering Laboratory?

S.S.:NSF is always interested in funding the best science. But the question is, “Can we afford it in the current climate?” The science board also wondered if NSF has the capacity to run a major facility like this. NSF doesn't run national labs. We're still interested in supporting the basic science. But maybe we'll be able to partner with other federal agencies.

Q:Did Congress make a mistake by prohibiting NASA and OSTP from scientific collaborations with China?

S.S.:[Congress] didn't say anything about NSF. … [Presidential science adviser] John [Holdren] can speak for OSTP. None of the things we do are proprietary or classified. We are a basic science agency, and we are in a different place than other mission agencies.… So far, we have not seen any impact from the congressional language.