News this Week

Science  27 Nov 2009:
Vol. 326, Issue 5957, pp. 1172
  1. Biotechnology

    Bankruptcy Won't Stop deCODE, Says Its Founder, Stefánsson

    1. Jocelyn Kaiser

    When the Icelandic company deCODE genetics Inc. filed for bankruptcy last week, many observers saw it as a bleak illustration of how hard it is to profit from research on the human genome. But deCODE and its flamboyant leader, Kari Stefánsson, aren't going away just yet. The company will continue operations with a loan from a potential buyer. And Stefánsson says he hopes to stay on as leader of deCODE's hunt for disease-causing genes.

    Stefánsson founded deCODE in 1996 based on the controversial notion of collecting genetic data on Iceland's citizens, combining them with medical and genealogical data and mining this biobank for disease markers. Although deCODE's research has been a roaring success, generating many high-impact papers, the company's efforts to make money from new drugs and genetic tests have failed. For the past year, deCODE has been offering some of its components for sale.

    What next?

    Kari Stefánsson is planning a new genetics firm called … deCODE.

    CREDIT: IAN LANGSDON/REUTERS

    Last summer, deCODE was in discussions with the Wellcome Trust, a U.K. biomedical charity, about taking over support for the biobank (Science, 28 August, p. 1054). No deal emerged, however. Stefánsson denies rumors that deCODE's restriction on data sharing was an issue. The “fundamental reason” was that Wellcome wanted to run deCODE as a nonprofit research institution, which was not possible because of the company's legal obligations to pay a return to investors, he says. However, he “was moved by the way they reached out to us.”

    Instead, the company is trying a different way to survive. Last week, deCODE's U.S. parent company filed for Chapter 11 bankruptcy in Delaware, which means it will reorganize its debt and keep afloat for now. The company has a $14 million offer from Saga Investments for its drug-development and -discovery programs and for Islensk Erfdagreining, the deCODE subsidiary in Reykjavík that runs the biobank and genetic testing services. The parent company expects to be liquidated, however, and stockholders are unlikely to get any of their money back.

    The deal must first be approved by a court, and other bidders could step in. Stefánsson says that if Saga's offer prevails—he hopes to know by early January—he expects to serve as executive chair of a new company and president of research. Someone else will serve as CEO and lead commercial operations. “It will be called deCODE,” he says.

    Stefánsson's research plan is to move on to the next stage in the hunt for disease genes: the search for rare variants. It is thought that these variants may confer higher disease risk than those found so far and would provide new insights into the biology of disease. Stefánsson says that by mid-2011 he plans to sequence the complete genomes of 2500 individuals, which, combined with genealogical data, should be enough to find variants occurring in 0.1% of Iceland's entire population of 320,000 people.

    Some researchers say that because it is easier to find rare variants in a homogeneous population like Iceland's, the company stands a fighting chance of remaining a leader in this area. Disease-gene hunters have “tacked back to where the field started,” says Stephen Chanock, a geneticist at the U.S. National Cancer Institute.

  2. Fusion

    Schedule Concerns Delay ITER's Go-Ahead

    1. Daniel Clery

    The scientific and engineering team building the ITER fusion reactor failed to win an expected endorsement from the project's governing council last week. The council, which represents the seven international partners in the project—China, the European Union, India, Japan, South Korea, Russia, and the United States—sent the team back to do more work on the proposed construction schedule for the mammoth undertaking.

    ITER is an experimental reactor that aims to show that nuclear fusion, the power source of the sun and stars, could be harnessed to generate energy on Earth. A site has been cleared at Cadarache in southern France for construction, and ITER staff have been racing for months to get the final project baseline documents, which describe the design, cost estimates, and planned schedule, ready for the 18–19 November council meeting at Cadarache (Science, 13 November, p. 932). But some council members voiced concern that the schedule, which aimed to start the reactor by 2018, was not realistic and that there was too high a risk that some part of the immensely complicated effort could go wrong.

    A slip in the schedule would invariably mean increased costs, and the council is already concerned about budget estimates, which, sources say, may have doubled from €5 billion since the partners signed up in 2006. So the council told ITER staff to nail down more firmly the risks, both technical and organizational, involved in the schedule and come back in February with earliest and latest possible start-up dates. “Europe is very concerned about the risk of pushing ahead too fast,” says Steven Cowley, head of the Culham Centre for Fusion Energy in Abingdon, U.K. “Building this is arguably harder than building the [Large Hadron Collider] because everything is inside everything else. You better get it right.” Discussion of the cost estimates appears to have been put aside until the schedule has been resolved.

  3. Infectious Diseases

    Farm Fungicides Linked to Resistance in a Human Pathogen

    1. Martin Enserink

    A team of Dutch researchers has reignited a debate on the agricultural use of fungicides with a review in the December issue of The Lancet Infectious Diseases. The authors maintain that the massive use of fungicides to protect European orchards, vineyards, and grain fields may be contributing to resistance against drugs used to treat people with life-threatening infections of Aspergillus fumigatus. Although the overuse of antibiotics in animal husbandry is known to have caused resistance in the human population, this would be the first time a similar link is found between farm use of fungicides and human health.

    Deadly mold.

    Invasive Aspergillus fumigatus infections can be fatal.

    CREDIT: CDC

    If true, the authors warn ominously, that “confronts us with a major challenge with worldwide dimensions.” But Herbert Hof, director of the Institute for Medical Microbiology at the University of Heidelberg in Germany, accuses them of crying wolf, saying the paper amounts to “publicity seeking” by frightening the public “in the way horror films do.” The group does have its supporters, however. David Denning of the University of Manchester, who heads the United Kingdom's National Aspergillosis Centre, says “they have a very strong case.” The leader of the team, Paul Verweij of Radboud University Nijmegen Medical Centre in the Netherlands, concedes that they haven't yet clinched the case, but he says enough evidence has accumulated to issue a warning.

    A. fumigatus causes infections, sometimes fatal, primarily in people with compromised immune systems and certain diseases, such as chronic obstructive pulmonary disease. Patients are thought to become infected when they inhale spores of the fungus, which are ubiquitous in soil. Drugs of a class called azoles are doctors' mainstay, and resistance has long been known to crop up in individual patients. The mutations in the fungus that cause the resistance usually differ from one patient to the next; in a paper published in July, for instance, Denning's team reported finding 18 different mutations in an Aspergillus gene called cyp51A in 30 patients in the United Kingdom.

    But Verweij's team has found something strange in resistant Aspergillus strains in the Netherlands: In 94% of the isolates from his own hospital and 69% of those from other Dutch hospitals, the resistance was caused by a single pair of mutations—a point mutation in cyp51A and a so-called tandem repeat in the gene's promoter. To Verweij, that similarity points to a new scenario: that all the patients breathed in spores that were already resistant. That's why he believes there's an environmental cause.

    Farmers' friend.

    Azoles are used to protect a wide variety of crops from fungi.

    CREDIT: HENRY ARDEN/GETTY IMAGES

    Azoles are used to ward off a range of plant pathogens and are applied on 50% of Europe's grain and grape acreage, says plant pathologist Gert Kema of Wageningen University in the Netherlands, a co-author of the paper. Much smaller amounts are used in the United States, where farming is less-intensive and spraying is less cost-effective. But the compounds are popular in other parts of the world as well, he says.

    The risk that heavy agricultural use of azoles might lead to resistance problems in people has been debated for years. In 2002, an expert panel for the European Commission concluded that it was unlikely. But since then, the evidence has been building, Verweij says. The resistant fungus found in patients is also resistant to certain agricultural fungicides, which is suggestive of a link. And in a paper published in June, his group showed that resistant Aspergillus could be isolated from soil in flower beds close to hospitals and in commercial compost, leaves, and seeds bought at a garden center. Thirteen of 15 of these environmental samples also had the two mutations seen in clinical isolates.

    In an e-mail to Science, Hof called the authors “prejudiced” and said resistance in fungi is unlikely to become a major public health problem because unlike bacteria, fungi don't swap resistance genes. Dominique Sanglard of the University Hospital in Lausanne, Switzerland, on the other hand, says the Dutch researchers seem to be on to something real, although many questions remain. A key step is to show that one or more of the azole fungicides—at least 30 of them are on the market—can actually trigger the mutations in A. fumigatus seen in hospitals, says Verweij; that study is already under way.

    And what if the link is proven? Verweij says a ban on certain fungicides could be an option. The team has been talking to several fungicide producers, and “they aren't very keen on studying this further,” he says. A spokesperson for Syngenta, a major azole fungicide producer, says that resistance may have arisen in other ways—such as azole use in cosmetics—and that the company is “not convinced” of a causal link.

  4. AIDS

    Asia Grapples With Unexpected Wave of HIV Infections

    1. Dennis Normile

    When physician Edsel Salvaña discovered earlier this year that new AIDS cases and HIV infections at his clinic in the Philippine General Hospital in Manila were running nearly double the 2008 rate, he was concerned. When colleagues at other clinics began reporting the same phenomenon, he grew alarmed. “It seems like HIV is starting to get out of hand,” Salvaña says.

    Not just in the Philippines. Across Asia-Pacific, a region so far largely spared the worst of the AIDS epidemic, HIV infections are rising rapidly, primarily among men having sex with men (MSM). In Hong Kong, Taiwan, Singapore, and Japan, where reporting is mandatory and trends can be tracked over time, HIV infections among MSM more than doubled between 2003 and 2007. Studies cited in “The global epidemic of HIV infection among men who have sex with men” in the July issue of Current Opinion in HIV and AIDS by Frits van Griensven, an epidemiologist at the U.S. Centers for Disease Control and Prevention's Bangkok office, and colleagues put HIV infection rates in MSM at about 30% in Bangkok and Yangon, more than 15% in parts of India, and more than 5% in Beijing. In the Philippines, the number of new HIV infections rose from 210 in 2005 to 549 in the first 9 months of 2009, with the proportion of those infected through homosexual contact jumping from less than 40% to more than 70%. The numbers “are pretty frightening,” says van Griensven, who says the statistics capture only a portion of those actually infected. In the Philippines, says Salvaña, most infections are identified only after an individual develops AIDS symptoms.

    Be safe.

    The Philippine Red Party kicked off its HIV awareness campaign with a benefit concert.

    CREDIT: PHILIPPINE RED PARTY

    Recognizing a worsening problem, the World Health Organization (WHO) in late September decried the “slow, fragmented and insufficient” anti-HIV efforts in the Western Pacific. With this concern in mind, the U.S. Agency for International Development and the United Nations Development Programme this week sponsored a meeting in Bangkok to bolster the region's HIV prevention, treatment, and care for MSM.

    The situation is likely to get worse before it gets better. Due to “significant levels of stigma, discrimination, and criminalization [of male homosexuality], there has been almost no investment” in some countries for interventions targeting this group, says Shivananda Khan, who heads the Naz Foundation International in Lucknow, India. “It is a perfect scenario for a major concentrated epidemic.”

    Unlike the AIDS epidemic in sub-Saharan Africa that has battered whole communities, Asia-Pacific cases are concentrated in three high-risk groups: IV injecting drug users, commercial sex workers, and MSM. “It took several years for the international community to fully understand why,” says Massimo Ghidinelli, WHO Western Pacific regional adviser in HIV/AIDS and Sexually Transmitted Infections. Behavioral studies and computer modeling indicate that the epidemic in Africa is sustained by men and women who often have multiple concurrent partners and change partners frequently, Ghidinelli explains. Throughout much of Asia-Pacific, he says, individuals may have several partners over time, but they typically end one relationship before starting another. And in parts of Asia, women tend to have one or at most a few partners throughout their lives. “The dynamics to maintain and amplify an epidemic [outside the risk groups] are not there,” Ghidinelli says. Another factor keeping infection rates low in the Philippines is widespread circumcision, which evidence shows inhibits infection.

    Taking off.

    Unprotected male-to-male sex is driving an alarming rise in HIV infections in Asia-Pacific.

    CREDIT: (SOURCE) FRITS VAN GRIENSVEN/PHILIPPINES DEPARTMENT OF HEALTH

    Although national HIV infection rates are still very low in Asia-Pacific, in MSM they are skyrocketing. The rates are “similar to how quickly they went up among female sex workers or injecting drug users 20 years ago,” says van Griensven. Even if the epidemic is confined to high-risk groups, Ghidinelli says, rising numbers of HIV-infected individuals could swamp health services and strain budgets of developing countries.

    Cultural factors complicate the issue. Some countries, such as Thailand, tolerate homosexuality, whereas in Malaysia and elsewhere it is a criminal offense. Although prosecutions are rare, laws banning homosexual acts make it difficult to fund interventions. Another factor is that in several Asia-Pacific countries, men who dress and act like women are common partners for men who don't consider themselves homosexual, Khan says. Denial and social marginalization mean that only an estimated 4% of the region's governmental spending on HIV/AIDS targets MSM, and interventions reach only 9% of this population. A 2008 report by the United Nations Joint Programme on HIV/AIDS forecast that without more aggressive measures, MSM could become the primary reason for new HIV infections in Asia, reaching a million cases a year by 2020.

    The situation is not grim everywhere. Some countries are reporting a leveling off of new HIV infections, says van Griensven. Last year, he says, Hong Kong and Taiwan cut new infections through “a bombardment of interventions.” Under Hong Kong's HIV/AIDS strategy adopted in 2007, the government expanded its own efforts and funded community organizations to study homosexual behavior, promote risk awareness and safer sex, and launch media campaigns to erase the stigma of being HIV-positive.

    Although some governments are waking up to the problem, Khan says, others are in denial. The Philippines is coming around thanks to Salvaña and his colleagues, who kicked off a new HIV/AIDS awareness campaign with a 5 September benefit concert in Manila. They are following up with school visits and plans to pressure the government to make HIV/AIDS intervention a priority. “This is our window of opportunity,” says Salvaña, “if it hasn't passed yet.”

  5. Newsmaker Interview

    Carlos Minc Pushes a Bold Agenda As Brazil's Environment Chief

    1. Antonio Regalado*
    Enforcer.

    Carlos Minc at a government raid in June near Santarém, Brazil, with illegal timber.

    CREDIT: JEFFERSON RUDY

    BRASÍLIA—Carlos Minc has a reputation for bold strokes. During Brazil's military dictatorship, he was accused of helping an armed leftist group make off with a 350-kg safe belonging to a corrupt politician. The reputed haul: $2.5 million. Minc was tortured and jailed and spent years in exile. Now Minc, who became environment minister in 2008, is again in the spotlight, this time for his role in engineering Brazil's announcement on 13 November that it would voluntarily make deep cuts in its greenhouse-gas emissions.

    As the first major emerging economy to promise cuts, Brazil could seed a diplomatic initiative at December's United Nations summit on climate change in Copenhagen, where countries are attempting to forge a replacement for the expiring Kyoto Protocol. So far, China and the United States, the world's largest emitters, have refused to endorse specific targets. But other countries—including South Korea, which announced a plan for 30% cuts by 2020—have joined Brazil in calling for action.

    A 58-year-old geographer rarely seen without his trademark embroidered vest, Minc has a reputation as a media-savvy green leader with pragmatic instincts. He won industry applause when he quickly approved a huge petrochemical plant. But he's successfully pressed for tougher action against deforestation, posing with seized timber or jumping on a tractor to knock down illegal charcoal furnaces. Science caught up with Minc in Brasília to ask him how he persuaded Brazil's president, Luiz Inácio Lula da Silva, to adopt voluntary emissions cuts. His answers have been edited for brevity.

    Q:Whom do you consider the most influential environmentalist in the world today?

    C.M.:I think it's the scientists of the Intergovernmental Panel on Climate Change. The positions that the IPCC took showed people for the first time that global warming is not a fiction and created a global clamor around the biggest planetary crisis civilization has faced.

    Q:What is Brazil's mitigation plan?

    C.M.:We want to reduce greenhouse emissions by 36 to 39% by 2020, which will actually take us back to where we were in 2003. … A year ago, we didn't have a climate plan or emissions goals, even though Brazil is the fifth or sixth largest emitter.

    Q:How did you persuade Brazil's president to agree to the plan?

    C.M.:We worked with the scientific community and showed that our mitigation steps, like expanding no-till farming and recuperating degraded land, wouldn't freeze our economy and that they didn't interfere with the creation of jobs or the reduction of hunger and inequality.

    Our diplomats worried that if we adopted aggressive limits, we would embarrass our allies, who aren't reducing emissions. India, for instance, is going to double them. But after a lot of discussion with the environment ministers of China, India, and South Africa, they told me they wouldn't be offended if Brazil went ahead, so long as it was clear we were not demanding that they do the same thing. They wanted to make sure our criticisms would be directed more at countries like the U.S., which are major emitters and not doing their homework. So I explained that to the president.

    Q:How long did it take to convince the president?

    C.M.:Two months. I explained to him that Brazilian society, even the industrial sector, was asking for this, and if we didn't act, it could lead to frustration domestically. Secondly, there was a chance that Copenhagen would be a failure. And Brazil, under no conditions, could associate itself with failure. We had to be a breath of oxygen, of renewable energy, for Copenhagen. So then President da Silva, who is not a scientist but is a great statesman and highly intuitive, sniffed out the best path: that what is good for ecology is also good for him politically, as much internationally as domestically.

    Q:How do we know Brazil's mitigation plan is real and not mere talk?

    C.M.:Half of our 39% emissions cut will come from the Amazon—reducing deforestation by 80%. We're starting with a baseline of 19,500 square kilometers [of forest lost annually] between 1996 and 2005. This year, we already got to 7500 square kilometers, the lowest level of deforestation in 21 years.

    Q:How are you reducing deforestation?

    C.M.:I've participated in 28 raids in the Amazon during the last 17 months. When we discovered cattle in environmental reserves, we auctioned them off for the government's antihunger program. I said illegal cattle will turn into barbecue for the poor. People thought I was kidding. We've already donated 20,000 head of cattle to prevent environmental criminals from enriching themselves. The other side is, you need to provide alternatives for sustainable forest management. We established minimum prices for 10 forest products. Just punishing people doesn't work.

    Q:Two days after Brazil's announcement, the U.S. and China said no climate treaty was possible at Copenhagen. Your reaction?

    C.M.:It was frustrating. I think the citizens of those countries need to speak out forcefully and not accept those positions as inevitable.

    • * Antonio Regalado is a writer in São Paulo, Brazil.

  6. Science and the Stimulus

    Science and the Stimulus

    1. Jeffrey Mervis

    An $18 billion burst of funding from the $787 billion American Recovery and Reinvestment Act is nurturing U.S. research. Where did it go, and is it being spent wisely?

    What's the best way for the U.S. government to spend $18.3 billion on basic research? The question may sound like a scientist's dream. But it's actually an ongoing experiment that began when President Barack Obama signed the American Recovery and Reinvestment Act (ARRA) less than a month after taking office.

    The Recovery Act—also known as the stimulus package—allocated $787 billion across the federal government to help lift the country out of the recession. Agencies were told to spend it quickly—before 30 September 2010—and to focus on creating jobs. But the investments are also supposed to help make the country more competitive in the long run.

    The huge research windfall—the National Institutes of Health (NIH) was given $10.4 billion, the National Science Foundation (NSF) $3 billion, and the Department of Energy (DOE) received $2 billion for basic research—presented these agencies with a unique opportunity to catch up from previous shortfalls. (Several other agencies received lesser amounts for science, and DOE also received tens of billions for various energy programs.) But it also put pressure on them to find ways to avoid a disruptive boom-and-bust cycle. The 407-page legislation sets out general rules for everyone to follow, with plenty of leeway for individual agencies. This package examines what the three leading science agencies did with that flexibility and how their choices will leave a deep imprint on U.S. research for years to come. The final story in the package examines a controversial area of research jump-started with $1.1 billion in stimulus money: comparative evaluation of medical treatments (p. 1183).

    How it happened

    Why did the Recovery Act include so much money for science? As a candidate, Obama had talked about the need for an economic stimulus package that included research investments, and his transition team began filling in the details almost immediately after Election Day. Democratic leaders in Congress had their own ideas, dating back to the Innovation Agenda drawn up in 2005 by Representative Nancy Pelosi (D–CA) and others before Democrats won control of Congress and Pelosi became Speaker of the House of Representatives. Both groups sought input from the scientific community, which was happy to provide lists of construction-ready projects and advice on broader areas to fund.

    On 15 January, the House put forward its version of the legislation, and its research provisions survived mostly intact after negotiations with the Senate. “We knew there would be competition for the dollars, but we also thought our priorities would compete favorably with any other request because we were all about the future,” Pelosi told a friendly audience of university administrators and research advocates last week.

    The agencies also did their part. NSF Director Arden Bement, serving a 6-year term that runs until November 2010, had testified repeatedly before Congress that the agency had a $2 billion backlog of highly rated proposals (see p. 1181). Raynard Kington wielded less clout as acting NIH director, but NIH's final tally vastly exceeded what most agency officials had expected thanks to the efforts of Senator Arlen Specter (see p. 1179). DOE's lame-duck political appointees were not involved in any negotiations. But the final bill largely achieved funding levels for science that the department had requested in previous budgets, helping incoming Energy Secretary Steven Chu get off on the right foot. It also launched one of his priorities, a new energy research agency created by Congress that the Bush Administration had opposed (see p. 1177).

    Once they received the money, the three science agencies took different approaches to spending it. DOE bankrolled a lot of infrastructure projects, especially at its national labs. NSF chose mostly to fund its backlog of good ideas. NIH did that, too. But it also held two major competitions aimed at pushing scientists in new directions. Despite short turnaround times, the solicitations generated a staggering 26,000 proposals.

    The president's science adviser, John Holdren, was an adviser to the transition team during the negotiations over the Recovery Act and didn't take office until a month after the bill was enacted. But he gives his Administration colleagues a thumbs-up on the decisions they've made. The stimulus money is “addressing pressing national needs” in fields ranging from clean energy and climate change research to science education, Holdren says, as well as responding to the “pent-up demand in the community.”

    Holdren's predecessor, John Marburger, gives highest marks to DOE's preference for funding construction projects and large instruments. “If you just have a burst of funding,” he says, “it makes a lot of sense to use it on capital projects [rather than grants] because it doesn't create the same longtime commitment to people and cause as much disruption when it ends.” He thinks that NSF's decision to boost success rates by funding a higher percentage of worthy proposals “was probably the easiest route and a good one.” But he worries about the long-term impact of NIH's decision to hold new competitions. “NIH has the most difficult problem [after soliciting] a huge amount of proposals and raising expectations,” says Marburger, who played no role in negotiating the size of the package. “We'll have to see if they got it right.”

    Science at work.

    House Speaker Nancy Pelosi (far right) and Representative Rush Holt (second from left) helped university officials celebrate a new Web site touting the research achievements of the Recovery Act.

    CREDIT: GREG SCHALER/GREGSCHALER.COM

    Holdren shares that concern about what happens after the stimulus money is spent. He asserts that “agencies are generally doing well in managing their stimulus spending to ensure a smooth transition to the post ARRA-era. … [But] will these strategies be enough to avoid falling off a cliff in the future? Not entirely, simply because the size of the investment makes some dislocations inevitable after the money runs out.”

    Adopting the same metaphor, Pelosi says that “falling off a cliff is not what we had in mind when we passed” the Recovery Act. And she doesn't think it will happen. “We know that we need to sustain the effort, or increase it, in both the life sciences and the hard sciences,” she says. “And no one is more aware of that need than the president.”

    The White House has made it easy for the public to keep score, with a Web site, recovery.gov, based on data that recipients provide quarterly to their funding agency. A compendium of anecdotes from the grass roots about research projects that address national priorities is available at scienceworksforus.org, a new Web site created by a coalition of universities.

    Those snapshots from academia and national labs are intended to sustain support for basic science as Congress races to complete work on the 2010 budget and gears up for what is expected to be a very difficult 2011 budget cycle. Last week, Representative Bart Gordon (D–TN), chair of the House Science and Technology Committee, warned research advocates of the tough road ahead. “The Recovery Act was an anomaly,” Gordon explained. “Now we're back into the regular appropriations cycle, and there's a consciousness we've got to get the deficit down.” His advice? “We have to get the band back together.”

  7. Science and the Stimulus

    Shovel-Ready Science Drives DOE Decisions

    1. Jeffrey Mervis

    The Recovery Act enhanced the ability of the Department of Energy's national laboratories to tackle big problems and got the Advanced Research Projects Agency-Energy off to a fast start.

    In the beginning were the lists.

    Candidate Barack Obama had talked about a massive government-spending program to revive the ailing economy, and after the election his transition team moved quickly to flesh out the idea. Sensing an opportunity, a handful of prominent physicists and science lobbyists compiled a list for Congress and the new Administration of all the “shovel-ready” research infrastructure projects at the Department of Energy (DOE)—those approved and ready to go out for bids.

    A similar exercise was taking place within DOE itself. Patricia Dehmer, then acting head of the DOE Office of Science, asked the office's six associate directors to give her a list of projects that satisfied two mandates that would appear in the enacted American Recovery and Reinvestment Act: to create jobs, and to provide the scientific and technological base needed for long-term economic recovery. Dehmer added two related criteria. “It had to be high-priority research and construction that was shovel-ready so we could move quickly,” explains Dehmer, now back as deputy director since the appointment of William Brinkman to head the science office. “And no, or few, out-year mortgages. I didn't want to reach a cliff in 4 or 5 years.”

    Two years of tight DOE science budgets had created quite a backlog of approved but unfunded buildings, large instruments, and other research improvements at DOE's 10 national laboratories and various user facilities. The staff-driven list carried a price tag of $5 billion. The community's list, which included projects supported by the National Science Foundation (NSF) and the National Institute of Standards and Technology, totaled twice that amount.

    An energy boost.

    Stimulus funding is accelerating projects in DOE's science pipeline and supporting two rounds of awards at a new research agency.

    CREDIT: SOURCE: ARRA

    Both were put to good use. Congress used the community's list as a guide in deciding to give DOE's science programs $1.6 billion in the final bill. Another $400 million went to the Advanced Research Projects Agency-Energy (ARPA-E), a new research entity housed within the secretary's office. ARPA-E is a favorite of Energy Secretary Steven Chu, who sees it as a way for the country “to hit a few home runs” as it tries to reduce its dependence on foreign oil, curb greenhouse gas emissions, and transition to a low-carbon economy. Even before President Obama signed the legislation on 17 February, however, Dehmer had whittled down her list to fit the expected funding level and obtained approval from Chu, who had been in office for only a few weeks. “We talked through them, and he accepted the recommendations I made,” she says.

    About three-quarters of the spending was unveiled in March. (Dehmer says a second round of projects, announced in August, needed more time to work its way through the White House approval process. But the belated announcement had nothing to do with the merits of the projects themselves.) Most of the money went to facilities, buildings, and instruments at the various labs, with the expectation that it would be spent before 30 September 2010.

    The use of the recovery money to speed up projects already in the agency's queue is expected to pay both scientific and fiscal dividends. Of the $90 million received by the SLAC National Accelerator Laboratory at Stanford University, for example, $33.6 million went to help outfit its newly opened Linac Coherent Light Source (Science, 9 October, p. 221). “The LCLS is the future of this lab,” says Director Persis Drell. “And having to wait for the instruments to come would have been very frustrating, because we want to get the science going as quickly as possible.”

    More than managing.

    As acting head of science, Patricia Dehmer drew up the funding list and made sure the money got out the door.

    CREDIT: COURTESY OF BROOKHAVEN NATIONAL LABORATORY

    The $65 million that Oak Ridge National Laboratory in Tennessee received for its new chemical and materials sciences building means that hundreds of scientists will be able to move into their new digs sooner, says Associate Laboratory Director Thomas Mason. By going out for bids in a slow economy and with the money in hand, he says, Oak Ridge managed to get an extra 1850 square meters of laboratory space at no additional cost.

    Not all of the recovery money is going into infrastructure. And there are even exceptions to Dehmer's rules about spending the money quickly and avoiding mortgages. The biggest involves a program launched in 2008 by Dehmer's former boss, Raymond Orbach, called Energy Frontier Research Centers. Designed to encourage multidisciplinary work on the country's toughest energy challenges, the program was budgeted at $777 million over 5 years. But the Office of Science's 2009 budget was so tight that it could scrape together only $100 million to seed the 46 centers. To accelerate their progress, $277 million in recovery money is being used to fully fund 16 of the university-based centers. The rest will be funded out of DOE's annual budgets for 2010 and beyond. And Dehmer says the Basic Energy Sciences program will have to find money from its budget to pay for any centers it wants to continue after their initial 5-year run.

    DOE is also wading into graduate education for the first time. “We wanted to begin a program in which graduate education was a part of what we did, and we felt that graduate fellowships would attract young people to our portfolio,” says Dehmer about the first-time, $12.5 million competition. “But we just didn't have the money to do any more.”

    Another $85 million of the Recovery Act funds has been earmarked to support early-career scientists at universities and at DOE's own national labs. The new DOE program is modeled after NSF's CAREER awards, with each program office supporting its own cadre of young scientists. “When you have a gold standard, you try to emulate it,” says Dehmer. She says DOE hopes that both the graduate fellowships and CAREER awards will reach a “steady-state level” of 400 scientists.

    Building boon.

    The Recovery Act has meant a $65 million head start for this $95 million chemical and materials sciences facility at Oak Ridge National Laboratory.

    CREDIT: JASON RICHARDS/OAK RIDGE NATIONAL LABORATORY

    Although DOE's process of allocating its Recovery Act money was opaque to outside scientists, the community seems very satisfied with the results. “I don't know what happened within DOE,” says Michael Lubell of the American Physical Society in Washington, D.C., which coordinated the community effort. Once the lists had been compiled, he says, “it was out of our hands. But my sense is that everything that was urgent and that was ready to go got funded. At least I haven't heard anybody complain.”

    Indeed, directors of several labs that benefited from the recovery money are applauding loudly. “They knew where they wanted their scientific program to be going,” says SLAC's Drell. “They do an extremely good job of looking ahead.”

    Chu knows that Congress is not likely to be as kind to DOE's budget as it was during his first year in office. But armed with the president's promise to double the Office of Science's budget by 2016, he's optimistic that DOE research will not suffer as the Administration attempts to trim overall federal spending.

    “It's a flat overall budget,” Chu says of rumors already circulating about the president's 2011 budget request. “But [research] is where the federal dollars can go the furthest. And that's why the president is calling for a 10-year doubling of the science budgets despite the fact that, if the DOE budget is flat and you're doubling the Office of Science budget, then you'll have to take it from someplace else [within DOE]. And I'm supportive of that.”

  8. Science and the Stimulus

    NIH Hopes Stimulus Isn't a Roller-Coaster Ride

    1. Jocelyn Kaiser

    A once-in-a-lifetime increase is a lifesaver for thousands of scientists. But will it also give them a false sense of hope?

    Stem cell researcher Michael Kyba hit the jackpot this year. Against daunting odds, Kyba won three research grants funded by the $10.4 billion the National Institutes of Health (NIH) received from the American Recovery and Reinvestment Act. The grants will expand his work at the University of Minnesota, Twin Cities, on how embryonic stem cells become blood cells. He's also leading a new $2 million, multi-institution collaboration on using stem cells to study and treat muscular dystrophy. Taken together, the awards will double the size of his lab.

    “I absolutely didn't expect all these grants to be funded,” says Kyba, who is now scrambling to hire three technicians and three postdocs. But there's a caveat, he points out: “It's only for 2 years.”

    Spreading the wealth.

    Extramural scientists and facilities are benefiting from a combination of new awards, supplements, and second chances.

    SOURCE (TOP TO BOTTOM): ARRA; NIH (DATA AS OF 26 OCTOBER 2009)

    At universities across the United States, and at the NIH campus in Bethesda, Maryland, officials and scientists are taking stock of a once-in-a-lifetime moment in U.S. biomedical research. The stimulus money has kept afloat the labs of thousands of investigators whose proposals had just missed the regular funding cutoff, as well as supporting novel research ideas, new investigators, summer students, and large technology projects. “It's unprecedented, and it couldn't have come at a better time,” says Steven Fluharty, vice provost for research at the University of Pennsylvania, which has received $143 million from the NIH windfall.

    Raynard Kington, who was interim NIH director from last fall through mid-August, lauds the “group psychological benefit” of increasing NIH's regular budget of $30.5 billion in 2009 by roughly one-third—as well as the “intellectual jolt” that the stimulus provided. “I think it turned out incredibly well,” says Kington, once again deputy NIH director since the appointment of Francis Collins as director.

    Two aspects of the NIH stimulus funding have attracted particular attention. First, it dwarfs the amount every other federal research agency received. Although some community leaders were concerned initially that it might be too much money to digest—and remain worried that it has set the stage for disaster in 2 years—most have embraced the argument that the increase simply allows the agency to recover from a string of flat budgets. “Steady multiyear budget commitments would be better policy in the long run, but to have not funded NIH during this economic crisis would have been worse public policy,” says Elias Zerhouni, who stepped down as NIH director in fall 2008. “We would have lost a lot of young scientists and good research.”

    Second, NIH chose to hold new competitions for some of the funds rather than drawing from a pool of proposals already in-house, as its sister research agencies have done. That decision triggered a tsunami of applications that led to a projected 1% success rate for the most prominent program, called Challenge Grants. (The actual rate was 4% after NIH institutes quadrupled the initial allocation.) By growing its portfolio, however, NIH also increased pressure on subsequent budgets, because most of those additional grantees are expected to apply for renewals in 2011 and 2012.

    The combination of a huge bolus of money and the additional mouths to feed has left many scientists wondering about the real impact of the stimulus spending on the health of the U.S. biomedical research enterprise. “I'm sort of back up in buying power to where I was 5 years ago,” says Gerard Evan, a cancer biologist at the University of California, San Francisco, about his $465,000-a-year supplement. “It's great, but the system's still sick.”

    “We gulped”

    Although the size of the stimulus may have been a shocker, the idea of giving NIH a big spending boost was not new. In July 2008, senators Tom Harkin (D–IA) and Arlen Specter, the Republican-turned-Democratic senator from Pennsylvania, proposed a 1-year, $5.2 billion increase as part of a 2008 supplemental appropriations bill that was never enacted. That figure, developed with input from NIH, was designed to make up for losses to inflation since 2003, the final year of a 5-year budget doubling. It also provided some extra money for the National Cancer Institute. (Specter has been treated twice for Hodgkin's disease.)

    Ten-billion-dollar man.

    Arlen Specter insisted on a monster increase.

    CREDIT: EMILY JENSEN/AHC COMMUNICATIONS

    Shortly after the November election, lobbyists and some legislators began talking up a $1.9 billion increase for NIH. President Barack Obama's transition team, which included Collins and former NIH Director Harold Varmus, pushed for more. Specter's staff came up with two numbers—$3.4 billion and $10 billion. The latter number, spread over 2 years, was, like the earlier summer proposal, intended to give NIH the buying power that it had in 2003. In return, Specter wanted NIH to do something novel with the money. Kington says NIH agreed not to just fund more highly rated awards—“We wouldn't simply march down the pay line”—but also to solicit new proposals with short-term research goals that would “get us over some hurdle.”

    Specter eventually embraced the larger number, and it stuck. The final bill divided the money into $1.8 billion for construction and equipment and $8.2 billion for extramural research. NIH also received $400 million from another agency for research on the comparative effectiveness of medical treatments and procedures (see p. 1183). “We were very pleased. I never for a moment doubted that we would be able to thoughtfully spend the money,” says Kington. Another high-level NIH official, however, has a different recollection: “We gulped.”

    A frenzy to apply for the money followed. It was driven by the Challenge Grants—up to $1 million over 2 years—which were developed to address Specter's concern that the money be used for new ideas as well as existing projects. Lured by a 220-page solicitation that covered 15 broad topics, tens of thousands of scientists dropped everything to apply for the $200 million pot. “The strain on our campuses was acute,” says Patrick White, vice president for federal relations for the 62-member Association of American Universities.

    The total number of Recovery Act applications eventually topped 26,000, far exceeding what NIH receives for its usual thrice-yearly cycle of grant applications in which billions of dollars are at stake. Searching for ways to cope with the onslaught, NIH officials reportedly cracked down on any application that deviated even slightly from the guidelines. Molecular pathologist Anirban Maitra of Johns Hopkins University in Baltimore, Maryland, for example, was part of a Challenge Grant application that NIH rejected because one of the seven investigators exceeded by four the 10 allowable references to publications in his biographical sketch. “We spent so much time putting the grant together. We were sick to our stomachs,” Maitra says.

    A buzz of activity.

    Michael Kyba's lab is growing thanks to stimulus funding.

    CREDIT: © JASON REED/REUTERS

    What's next

    After working overtime all summer, NIH officials managed to disburse $4.35 billion in grants and $379 million in contracts before the 2009 fiscal year ended on 30 September. Because most recipients will receive a comparable amount in 2010, that means NIH has committed 90% of its Recovery money. What remains are some instrumentation and construction awards, plus a small amount for new programs.

    Not surprisingly, the money has had a huge impact at universities, say research deans. At Penn, for example, Fluharty says 11 of 23 faculty members on a bridge program funded by the university received NIH stimulus awards. The 1885 grants going to first-time investigators have also meant a big boost for younger faculty members.

    Besides these grants to individuals, NIH funded many big-ticket, one-off projects, such as $27 million to create a social network for scientists to find collaborators and share resources. The White House has calculated that more than $1 billion of the $8.2 billion spent on extramural research involves genomics studies, including $175 million for the Cancer Genome Atlas and $64 million to sequence the genes of 8000 participants in long-term heart and lung studies.

    The next challenge for investigators with recovery money is to meet NIH's goal of creating or preserving 50,000 jobs. Most universities have a readily available pool of qualified technicians. But the uncertainties of completing their graduate work and defending their doctoral dissertations make it harder to find potential postdocs quickly. Kyba says he will warn candidates that the job might end in 2 years.

    University administrators are also very worried about 2011. “We will have built [more] capacity; we will have hired people,” says Fluharty. “How will those jobs be maintained?”

    NIH is already worrying about the short-term impact of the stimulus on community expectations. Officials anticipate a possible bulge in grant applications in February, fueled in part by the fact that the 12-page limit imposed on Challenge applications will now also apply to standard R01 grants. That equivalency will make recycling rejected proposals a breeze.

    Unfortunately for those applicants, however, NIH has already spent its stimulus money. That means Collins must convince Congress that NIH's budget needs to keep growing at least at the rate of inflation. “My sense is that we can make the case by talking about the science, what's being done and what has already been done” on things such as improving survival rates for diseases, he said last week. And although Collins is concerned about the need to boost success rates, he's not planning to use it as his trump card. “I'm not sure it gets the attention of Congress … in the way the science does,” he says.

  9. Science and the Stimulus

    NSF Boosts Success Rates, But at What Price?

    1. Jeffrey Mervis

    Dipping into a backlog of highly rated proposals is a safe bet. But are there enough high-risk, high-reward ideas in the pot?

    Hilairy Hartnett got the bad news in January. The National Science Foundation (NSF) had turned down, for the third time, her application for a CAREER grant, a prestigious 5-year award for tenure-track faculty members who want to combine their research interests with their role as educators. Hartnett's idea to study how the Colorado River takes in and transforms carbon as it flows through the region on its way to Mexico had gotten high marks from reviewers. But her scores were never quite good enough to beat out the very stiff competition.

    So Hartnett, a geobiochemist up for tenure this year at Arizona State University, Tempe, decided to rework the idea and resubmit it as a regular proposal to NSF's geosciences directorate. She knew the odds weren't much better, but she had no choice: Researchers can apply only three times for a CAREER award. She also regretted losing the educational component, which would give undergraduates a chance to carry out complex environmental field studies and learn about an important natural resource in their state.

    But before Hartnett had done anything, national politics came to her rescue. In May, she got a call from her program manager at NSF, asking if she was still interested in carrying out her CAREER project. Of course, she stammered. But why did it matter? What had changed?

    The answer, in short, was the $787 billion American Recovery and Reinvestment Act (ARRA), which was signed into law on 17 February. NSF's slice of the so-called stimulus bill added $3 billion to its regular $6.5 billion budget for 2009: $2 billion for research activities, $900 million for three different infrastructure programs, and $100 million for a handful of specific education and training activities (see top graphic). That huge increase was based on the repeated complaint from NSF Director Arden Bement in congressional testimony that the agency received billions of dollars'worth of good research proposals each year that it couldn't fund. Although Congress specified how NSF should spend the two smaller pots of money, it bowed to NSF's reputation for quality peer review by giving it great leeway in disbursing the largest component.

    Bement decided to use the recovery funds to whittle down NSF's huge backlog of highly rated proposals and raise success rates—improving the odds for applicants like Hartnett. Bement also told program officers to give priority to young investigators and to “high-risk, high-reward research.” The latter phrase is code for two important policy debates swirling around NSF. “High-risk” addresses concerns from Congress and the scientific community that NSF is too conservative in making its granting decisions. “High-reward” signifies that the agency's portfolio is relevant to important national needs, such as research on climate and energy, that are top priorities for the new Obama Administration.

    Bement's priorities were a trifecta of good news for Hartnett. She is a young (albeit at age 41 hardly inexperienced) investigator. Her CAREER proposal was technically still in play. And her project explores the link between terrestrial and aquatic ecosystems, important components in understanding the effects of climate change. “I was stunned, and I'm infinitely grateful,” says Hartnett, one of many researchers whose rejection letters were turned into grants once NSF received the recovery money. Coming on the heels of a 5-year, $389,000 NSF grant that expires in March 2010, the 5-year, $573,548 CAREER award will also sustain her lab. “It's dramatically changed my situation.”

    All told, NSF staffers spent an additional $165 million on the CAREER program, boosting the number of awards by 50%. (Each of NSF's seven directorates participates in the program, with the two largest, engineering and math & physical sciences, making the most awards.) What's more, some 45% of the grants funded with recovery money included at least one first-time grantee, a much higher percentage than normal and another perennial goal of NSF program managers. NSF has also calculated that 10% of the stimulus money (489 awards) has gone to energy-related research, with another 17% (800 awards) supporting climate-related research.

    Cashing in.

    Adding $2 billion to a $5 billion research account has given scientists a better chance of winning an award from any one of NSF's seven directorates.

    SOURCE (TOP TO BOTTOM): ARRA; NSF

    Bement's policies have had a spectacular impact on success rates. The NSF-wide average for competitive awards jumped from 25% in 2008 to 32% in 2009. The geosciences directorate tops the list, with a 44% success rate (up from 31% in 2008), and the rate for NSF's largest directorate, mathematics & physical sciences, climbed to 40% from 29%. (All numbers are for the fiscal year that ends on 30 September.)

    But those higher success rates may not last for long, warn some science lobbyists, if Congress fails to deliver on a promised doubling of NSF's budget over 10 years. “It's happened so many times in the past that the scientific community has come up short,” says Michael Lubell of the American Physical Society. Bement says he has faith in Congress and the Administration, pointing to what is likely to be an increase of almost 7% in 2010 and what he hopes will be a healthy 2011 request.

    The “summer from hell”

    Agencies are required to keep their recovery money separate from their regular appropriations so that the spending can be tracked more easily. But that doesn't mean the funds have to be spent on different programs. Some 307 of the 694 CAREER awards this year, for example, are funded with ARRA money. (That's up from 456 CAREER awards in 2008.) And NSF's engineering directorate was able to boost the number of $2 million grants it made this year for a signature program called Emerging Frontiers in Research and Innovation to 20, from 12 in 2008, by using ARRA money to finance seven of the awards.

    Mindful of the rules governing the use of recovery money, Bement decreed that all the projects it supported would be fully funded from the start, rather than receiving the money over several years. But he says that his real focus was on “the fact that we had four and a half months to spend $9.5 billion.” Pushing nearly 50% more money out the door before the 30 September end of the 2009 fiscal year translated into 15-hour days for program managers and budget officers across the foundation.

    On the money.

    Arden Bement made the case for boosting success rates.

    CREDIT: SANDY SCHAEFFER/NATIONAL SCIENCE FOUNDATION

    “It was the summer from hell,” recalls Jarvis Moyers, head of the division of atmospheric and geophysical sciences within the geosciences directorate. And despite all the extra work, Bement notes that “we didn't get a single nickel to cover our additional administrative costs.” One saving grace: NSF's decision not to hold any new competitions (except for two infrastructure programs) meant that the community didn't need to devote additional time to writing grant proposals or serving on review panels.

    NSF's bigger budget has increased political expectations that the agency will place more bets on the type of high-risk, high-reward ideas that have the potential to transform the scientific landscape—and eventually pay off big for the country. One program designed to do exactly that is called EArly-concept Grants for Exploratory Research (EAGER, which until January were called Small Grants for Exploratory Research, or SGER). The grants, which allow investigators to collect preliminary data on a promising idea, are green-lighted by a program officer and don't require external review. Bement has urged all directorates to spend up to 5% of their budgets on such awards.

    Program officers traditionally have resisted that suggestion to avoid further depressing already low success rates for their regular programs. And the influx of recovery money doesn't seem to have changed that mindset. Last year, for example, NSF funded 430 SGER awards, representing 0.6% of its research budget. (They are typically smaller than the usual NSF grant.) This year the combined total of the two grants rose to 502. But that's still less than 1% of the budget and far below Bement's target.

    Last month a House of Representatives science panel heard suggestions on how NSF and other federal agencies can do more to foster high-risk, high-return research. Richard McCullough, vice president for research at Carnegie Mellon University in Pittsburgh, Pennsylvania, suggested that NSF create a second program to supplement EAGER “so that, once a transformative discovery occurs, we can accelerate its development.” And he pointed out that his university, despite receiving $26 million in stimulus funding and millions more overall in fiscal year 2009 from NSF, has exactly one EAGER award.

    A fount of knowledge.

    Hilairy Hartnett shows students how to take a water sample from an acidic hot spring in Yellowstone National Park.

    CREDIT: ARIEL ANBAR

    Gerald Rubin, vice president for research of the Howard Hughes Medical Institution's Janelia Farms Research Campus in Ashburn, Virginia, wants NSF to go even further. “We fund people, not projects” at Hughes, Rubin explained, predicting that federal agencies would get a much bigger bang for their buck by doing likewise with a small slice of their budgets. As an example, he suggested giving $10 million over 5 years to each of the finalists for NSF's prestigious Alan T. Waterman Prize, awarded to the best U.S. scientist under 35.

    Bement doesn't think much of Rubin's suggestion. “As a federal agency, we have to be a bit more prudent,” he says. “That's not to say we don't fund people. But sometimes a person who has done outstanding work gets stuck in their own paradigm. … We are always on the lookout for stars, but only those who continue to twinkle.”

    Holding a new competition, like the one that National Institutes of Health conducted, would have been one way to attract fresh ideas. But that approach had two strikes against it as far as Bement is concerned: It would have depressed success rates and slowed down the process. “We felt that it was important to get as many grants out the door as possible,” he says. “So we took full advantage of what we had on hand.”

    As for whether NSF's overall research portfolio is benefiting society, Jeannette Wing, head of NSF's computer and information science and engineering directorate, has a ready answer. “We funded a project at Stanford University more than a decade ago to create a digital library,” she explains. “And on the last page of the final project report, it says, ‘and we founded a company called www.google.com.’”

    She hardly needs to finish the story. “An investment in one project at one university turned into a completely new industry that transformed society,” says Wing. “And you can't predict that.”

  10. Science and the Stimulus

    Medicine Under the Microscope

    1. Eliot Marshall

    A billion dollars in stimulus money will go to evaluating which medical treatments and procedures work best.

    Long-standing advice to all women in the United States that they should get a mammogram every year after age 40 was overturned last week. After combing through medical data and analyzing six models of disease progression, an expert panel declared that regular mammograms, which expose women to excess radiation and may lead to unnecessary surgery, are more harmful than helpful to someone younger than 50. Even after 50, the panel said, a mammogram every other year would be sufficient. The American Cancer Society and the American College of Radiology immediately rejected the new advice—as did Health and Human Services (HHS) Secretary Kathleen Sebelius the next day—recommending that women follow the familiar old rule.

    Such turmoil in the medical ranks could become more common if an evidence-rich kind of analysis backed by the economic stimulus bill takes off. It's known as comparative effectiveness research (CER), and it received a windfall of $1.1 billion in February under the American Recovery and Reinvestment Act. CER employs methods similar to the approach that produced the new advice on mammography.

    CER draws data from many sources to reach an evidence-based judgment on the value (or lack of value) of medical techniques and strategies. The process must be rigorous, according to a definition of CER hammered out in June by a federal coordinating group (www.hhs.gov/recovery/programs/cer/draftdefinition.html). Its scope is broad, ranging from comparing drugs in a clinical trial to studying behavior-modification methods to dissecting the impact of health policies. The aim is the same, however: to survey a patient's choices and determine which course works best. The results of a CER study are somewhat like a consumer's guide (see sidebar, p. 1184)—and often as confusing.

    Obama Administration officials are enthusiastic about CER and pushed for its inclusion in the stimulus bill as a way to “bend the curve” of health care spending. By this, they mean that it can spot ineffective and overused medical procedures. Armed with such information, they argue, patients and doctors will become more discriminating. In time, they hope, this will slow the growth of U.S. health care spending, which now stands at about $2.4 trillion per year, or one-sixth of the economy.

    CER proponents also hope to use the approach to analyze “real world” medical problems. This phrase suggests something different from classic randomized clinical trials, which generally exclude patients who don't fit a specific profile. CER studies, in contrast, may gather records from small clinics and observational studies, taking in people of all ages, including those with complex and overlapping medical problems. Proponents say this could deliver more practical information, more rapidly, than do randomized trials.

    “You can see why we are happy, proud, and excited,” says Carolyn Clancy, director of the Agency for Healthcare Research and Quality (AHRQ), which is at the core of the government's push for improving medicine. Her agency has been getting by since 2005 with about $30 million a year for CER, she says. Now the stimulus windfall has “bumped up” the CER portion to $300 million. The National Institutes of Health (NIH) and the secretary of HHS, working with AHRQ, will parcel out the remaining $800 million in stimulus money (see table).

    The plan is controversial. Some patient advocacy groups and physicians charge that CER studies could eventually be used to guide insurance and Medicare payments or to overrule a physician's judgment about what is best for the patient. CER has been denounced on blogs as a precursor to “medical rationing.”

    Key decisions about CER could be affected by the roiling debate. It's not clear, for example, whether the billion-dollar launch of CER in 2009 will be followed by sustained federal support. Nor has it been decided specifically how the government will oversee this research. “There have been open differences about how to frame the research—with some people wanting a more restricted scope and others trying to avoid burdensome restrictions,” says Steven Pearson, president of the Institute for Clinical and Economic Review at Massachusetts General Hospital in Boston.

    Relentless.

    U.S. health costs have been rising steadily and taking up an increasing share of the economy; leaders hope CER can help “bend the curve” downward.

    SOURCE (TOP TO BOTTOM): ARRA; NIH

    Spending the windfall

    With their pockets full of cash, the three agencies with CER stimulus funding began to plunk down commitments this fall. Clancy says the top priority at AHRQ is to pay for “evidence generation,” funding investigators to learn what happens to patients with similar ailments who undergo different treatments. Linked to this, Clancy says, is a push to build infrastructure by investing in clinical databases, sharpening analytical methods, and creating networks to disseminate findings.

    NIH was first out of the blocks. It has awarded 165 CER grants, totaling $350 million of the $400 million to be spent (projectreporter.nih.gov/files/ARRA-projects.xls). Like others, NIH is funding work on topics from a list of 100 questions drawn up in June by a panel of experts at the National Academies' Institute of Medicine. (www.iom.edu/en/Reports/2009/ComparativeEffectivenessResearchPriorities.aspx). NIH Director Francis Collins noted in October that much of this research is familiar: “Eighty-eight of the 100 priorities in the plan are already covered” by NIH-funded investigators, he said in a talk at AAAS (which publishes Science).

    Typical of the NIH winners is a $2 million project that will zero in on the use of advanced medical imaging, a controversial topic. New machines are being deployed rapidly, says Bruce Hillner, a physician-researcher at Virginia Commonwealth University in Richmond who's involved in the project. X-ray computed tomography, magnetic resonance imaging, and positron emission tomography (PET) are now used for many purposes, from checking out nonspecific “belly pain” to detailed monitoring of cancer as it progresses or recedes. “For more than a decade, the use of these technologies has increased 15 to 20% every year,” Hillner says. Studies have shown that specific uses have great value, but indiscriminate use may have penalties, such as triggering “futile surgery”—life-threatening operations that lead to no benefit. Furthermore, the imaging boom isn't driven strictly by medical evidence; it may also be fueled by “self-referral” by physicians who have a stake in imaging services.

    Worth it?

    An important question for comparative effectiveness research is whether medical scans are used appropriately.

    CREDIT: © ROBERT LLEWELLYN/CORBIS

    Hillner is co–principal investigator at a repository, the National Oncologic PET Registry (NOPR), that has gathered data from U.S. cancer-related PET scans since 2006. He's teaming up with Dartmouth Medical School researchers William Black and Anna Tosteson, who lead a new collaboration to review cancer imaging. Hillner says he plans to “work backwards” from the NOPR database, which was designed for this purpose, to see if physicians followed the cancer management plan they described when they sought reimbursement for a PET scan. Among the questions he'll be asking are: Did the plan change? What happened to the patient? How did PET affect surgery decisions, including futile surgeries? Did physicians generally use multiple overlapping technologies, or did they use only PET?

    Like NIH, which is putting nearly all of its money into research, AHRQ will invest $100 million of its $300 million in investigator-initiated clinical studies called CHOICE awards. It plans to make 10 of these at roughly $10 million apiece, running for 3 years each. For these, the White House has waived the rule that stimulus money be spent within 2 years. “They are big grants” for the field, says Tosteson.

    AHRQ hasn't announced the CHOICE winners as of yet. But its detailed spending plan, required under the Recovery Act, includes $48 million for patient registries, $25 million for evidence synthesis, $29.5 million for dissemination of results, and $20 million for training. (HHS hasn't released a list of grants or a spending plan.)

    How will findings be used?

    The plan to boost CER ran into flak early this year when opponents said studies might be used to cut back on specific treatments in an attempt to lower costs and ration medical care. Critics included well-known physicians, patient advocacy groups, and members of Congress.

    Evidence, please.

    Carolyn Clancy directs AHRQ, which funds research on what works in medicine.

    CREDIT: AHRQ

    One surprising blast came from the respected hematologist and The New Yorker writer Jerome Groopman and his wife, Pamela Hartzband, both of Harvard Medical School in Boston. Their 31 August editorial in The Wall Street Journal suggested that a national effort to define the best practices in medicine would end up describing only averages and not what's good for a specific patient. They warned that economic incentives intended to nudge doctors toward following national rules—as some would like to do—would mean that “federal bureaucrats are directing health decisions.”

    Advocacy groups have been outspoken, too. Tony Coelho, a former Democratic congressman from California who heads the new Partnership to Improve Patient Care, has kept up a steady drumbeat of warnings about the need to circumscribe CER. The group argues that CER is fine if used to inform patients and doctors, but it should not be used for “making centralized coverage and payment decisions or recommendations.” Coelho's group is supported by the Biotechnology Industry Organization, the Pharmaceutical Research and Manufacturers of America, and the American Association of Neurological Surgeons, among others.

    In response to such concerns, Congress decreed in a conference report on the stimulus bill that CER should not examine cost issues. And members of Congress specifically banned using such research to “mandate” changes in Medicare. The future use of CER hangs in part on whether this ban is continued. “Even without cost-effectiveness information,” says Harvard historian of science Jeremy Greene, an expert in this subject, “I think CE information is essential to improving the quality of our health care system.”

    The health care reform bills now before Congress may also determine how CER is managed. The House of Representatives–passed bill and the version drafted by Senate Democrats both seek to reduce friction over CER findings by ensuring that the government consults with stakeholders—patients, doctors, and industry representatives—before making big investments in CER or acting on research findings. But the House and Senate proposals differ on who calls the shots. The House plan would rely essentially on AHRQ to set research policies, with input from advisers. The Senate approach would vest authority in an independent, nongovernment corporation.

    Congress is treating the subject with caution precisely because CER promises a radical change in the way medical practices are evaluated, bringing a lot of new data to bear on decisions. And as the brouhaha over screening for breast cancer shows, new evidence isn't necessarily welcome.

  11. Science and the Stimulus

    A User's Guide to Cancer Treatment

    1. Jenny Marder*

    “Is my disease curable?” That's the first question patients usually ask after learning they have prostate cancer, says Patrick Walsh, a surgeon and urology professor at Johns Hopkins Medical Institutions in Baltimore, Maryland. “Then they want to know, ‘What are my options for treatment?’” Choose radiation or surgery—and risk severe side effects? Opt for no treatment—and risk having the cancer spread?

    Often, there isn't a clear answer. Imaging scans may not accurately identify the amount of cancer in the prostate. Experimental data comparing different treatments are nearly nonexistent. “So you lay out the side effects,” Walsh says. “You lay out the fact that you don't know whether surgery or radiation is better. … It's a very humble conversation.”

    Data slog.

    A review team led by Timothy Wilt (seated, left) pored over data from more than 700 prostate cancer studies.

    CREDIT: APRIL EILERS/VA MEDICAL CENTER, MINNEAPOLIS

    More than 200,000 men in the United States are diagnosed with the illness every year, making treatment options a prime candidate for review, according to William Lawrence, a medical officer at the U.S. Agency for Healthcare Research and Quality (AHRQ). Lawrence oversaw a comparative effectiveness (CE) review on prostate cancer commissioned by AHRQ in 2005, one of 18 the agency has done.

    Timothy Wilt of the Minneapolis VA Medical Center, the review's lead author, and eight colleagues compared the most popular treatment methods, including surgery, radiation, hormone therapy, and “watchful waiting.” They also looked at a few not-so-common options, such as cryotherapy, which rapidly freezes and thaws cancer cells to destroy them.

    The study, which cost $500,000, followed a standard course laid out by AHRQ, guided by questions from a group of “stakeholders” representing patients, radiation oncologists, urologists, and primary-care physicians. The nine reviewers slogged through mounds of evidence from more than 700 studies, assessed the strengths of doctors and hospitals, weighed side effects, and evaluated outcomes. Data on outcomes and side effects were culled from patient databases, surveys, and clinical trials. They encountered hurdles along the way: Countless definitions of erectile dysfunction and urinary incontinence made side effects tricky to compare. Randomized, placebo-controlled trials were lacking. The team searched for patterns, which they painstakingly graphed as a massive scatter plot, the size of each dot relative to the size of the study.

    In February 2008 they delivered their findings: No one treatment is superior. All have adverse effects. Fewer side effects developed among patients treated by surgeons and medical centers that had performed more surgeries. The reviewers also spotted a revealing pattern: Doctors are more likely to recommend the treatment they practice. Wilt says: “Surgeons recommend surgery, radiation oncologists recommend radiation therapy, and very few individuals recommend watchful waiting, even for men with relatively slow-growing tumors, despite the fact that evidence suggests that all three treatment options are quite acceptable. Both patients and providers would be better served by knowing this information and having it displayed and available to them.”

    Strong differences.

    An analysis of U.S. prostate cancer treatments by region showed that “watchful waiting” was least practiced in New England.

    CREDIT: APRIL EILERS/VA MEDICAL CENTER, MINNEAPOLIS

    Opinions of the review are mixed. Some say it provides important guidance to people struggling with complex decisions. AHRQ produced a pair of guides summarizing the review for doctors and patients. More than 15,000 people ordered the guides for the prostate cancer study, according to AHRQ. “Often, what happens when you get diagnosed with something is you're kind of shell-shocked and you want to read up,” says Jean Slutsky, director of AHRQ's Center for Outcomes and Evidence. These guides, she says, help patients organize their thoughts and understand the research.

    Others say the prostate cancer review illustrates the limitations of CE research. Walsh, who has published his own book, Dr. Patrick Walsh's Guide to Surviving Prostate Cancer, says the AHRQ clinicians' guide provides information that a doctor should already know, and the consumers' guide is full of questions: “They did their best, but I don't find it terribly helpful in the treatment of my patients.”

    Sean Tunis, director of the Center for Medical Technology Policy in Baltimore and an expert on CE research, agrees that the review fails to address some essential questions. It represents something that occurs commonly in CE research, Tunis says: “A lot of times people mistakenly think that you can do a systematic review of what's known, and you'll come to a conclusion on what's more effective or less effective, more expensive or less expensive. But most come to the conclusions this one did: The studies we'd like to have haven't been done.”

    Studies to fill research gaps need to be funded faster and tackled more efficiently, Lawrence says: “That's one area where I think you'll see more from us in the future.”

    • * Jenny Marder is a writer in Washington, D.C.

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