News this Week

Science  07 Jul 2006:
Vol. 313, Issue 5783, pp. 26

    Senate Prepares to Vote at Last on a Trio of Stem Cell Bills

    1. Constance Holden

    Senate leaders have formally agreed to allow a vote-possibly this month-on a bill that would allow federally funded researchers to work on newly derived lines of human embryonic stem (ES) cells. The bipartisan deal announced last week was painstakingly cobbled together over the past few months to placate opponents by including one bill that would promote “alternatives” to embryo destruction for obtaining stem cells and another that would outlaw “embryo farms.”

    Supporters of stem cell research have lobbied hard for an up-or-down vote in the Senate on a bill, passed in May 2005 by the House (H.R. 810), that would allow federally funded researchers access to cell lines derived after the presidentially imposed cutoff date of 9 August 2001 (Science, 3 June 2005, p. 1388). Last summer, Senate Majority Leader Bill Frist (R-TN) reversed his previous opposition to human ES cell research and said he supported H.R. 810. But as the months rolled by without a Senate vote, many stem cell boosters began to worry that Frist, a physician who is leaving the Senate at the end of the year for what is expected to be a run for president, might be dodging the issue for political gain.

    But it turns out that Frist, along with stem cell advocates Senators Arlen Specter (R-PA) and Tom Harkin (D-IA), has been working hard to win a so-called unanimous consent agreement that commits members to the terms of the vote. The last piece to fall into place, apparently, was convincing fellow physician Tom Coburn (R-OK) to drop his own “alternatives” bill in favor of the agreed-upon legislative troika. Frist's office says he intends to schedule a vote before the Senate goes into its August recess.


    Under the agreement, H.R. 810 will be buffered by two bills designed to appeal to opponents of embryo destruction. One (S. 2754), co-sponsored by Specter and Rick Santorum (R-PA), calls on the National Institutes of Health (NIH) to promote research on finding ways to derive pluripotent cells other than from embryos. The bill would only reinforce current NIH policies, NIH stem cell czar James Battey told senators last week at a hearing on the legislation. The other measure (S.3504), co-sponsored by Santorum and Sam Brownback (R-KS), prohibits trading in tissues from human fetuses “gestated [in humans or animals] for research purposes.” This is already prohibited under federal funding rulesnd wo auld in any case be ethically taboo for legitimate researchers. Because the bills are not mutually exclusive, the Senate could easily pass all three.

    The agreement has successfully divorced the matter of generating new cell lines (from excess embryos in fertility clinics) from an issue with which it has often been conflated: generation of cell lines through research cloning (otherwise known as somatic cell nuclear transfer). Earlier scenarios of how H.R. 810 might be brought before the Senate included a Brownback-sponsored bill that would outlaw all forms of cloning. Research supporters feared that President George W. Bush would veto H.R. 810 and sign the anticloning bill into law, leaving them worse off than under present circumstances.

    There are now 21 human ES cell lines available to federally funded researchers. But scientists want more: Cell lines get corrupted over time by genetic mutations; the available ones were all cultivated using animal feeder cells, which limits potential use for humans; and researchers want to be able to work with lines containing genes for specific diseases.

    Representative Mike Castle (R-DE), a prime mover in getting H.R. 810 through the House, predicts a “momentous” debate and praises Frist for his “thoughtfulness and commitment.” Adds Kevin Wilson of the American Society for Cell Biology in Bethesda, Maryland, “I was afraid he wasn't going to be able to get it through. The one thing we knew is it had to be a clean bill.”

    Each bill needs a filibuster-proof 60 votes to win passage. But Wilson notes that retaining the exact language that the House passed was also vital because any changes would force the bill into a conference with the House, where it could be swamped with amendments or delayed indefinitely.

    The Senate's willingness to take up H.R. 810, he and others note, also may reflect polls showing that the vast majority of the public supports it. Still, that may not be enough. White House spokesperson Blair Jones says Bush won't budge on the issue. “He does not believe we are forced to choose between science and ethics,” says Jones. “This crosses an important moral line.”


    International Standards Proposed for Stem Cell Work

    1. Gretchen Vogel

    TORONTO—Scientists who work on stem cells have proposed draft guidelines to set ethical standards for researchers around the world. The guidelines, which are the work of an international committee, lay out ground rules for work with embryos and the cells derived from them. The document also recommends ethical standards for obtaining sperm, eggs, embryos, or other cells from human donors.

    The guidelines are consistent with those set out by the U.S. National Academies last year (Science, 29 April 2005, p. 611), but “we extend and refine those principles” for the international community, George Daley of Harvard Medical School in Boston said at a meeting* here last week. Daley, who headed the drafting committee with 30 members from 14 countries, says the document should ease collaborations between scientists who live in regions of the world with different laws and local regulations regarding use of embryos or informed consent of tissue donors. The guidelines recommend that certain types of research, such as derivation of new embryonic stem cell lines or generation of chimeric animals, be subject to special review by an independent panel. In some cases, the panel may be at the investigator's institution; others might be governed by a regional or national review. The guidelines also set standards for sharing research materials including reagents, animal strains, and cell lines and urge scientists to deposit new cell lines at national or international cell banks.

    Committee members said their most intense debates concerned how to fairly compensate women who donate oocytes for research. People who donate bone marrow for research, for example, are usually paid for their time, discomfort, and inconvenience, but several committee members felt strongly that oocyte donors should not be offered any compensation beyond reimbursement for their expenses. In the end, the committee agreed that local review boards should ensure that compensation does not “constitute an undue inducement” but otherwise left the final decision up to local laws and practices.

    The committee plans to draw up template documents for material transfer agreements and informed consent for the donation of cells or embryos. Daley says such templates would have made the work dramatically easier as he and his colleagues prepared to begin human nuclear transfer experiments this spring.

    ISSCR members have 60 days to comment on the draft, which has been posted on the society's Web site. The committee hopes to issue a final document by the end of the year.

    • * International Society for Stem Cell Research 4th Annual Meeting, 29 June-1 July, Toronto, Canada.


    Four Genes Confer Embryonic Potential

    1. Gretchen Vogel

    TORONTO—One of the biggest questions in stem cell biology is how the cloning process manages to turn back the clock of differentiated cells, resetting them to their embryonic potential. Ideally, researchers would like to find a way to convert adult cells directly into embryonic stem (ES) cells—without having to create an embryo at all. At the ISSCR meeting* here, Shinya Yamanaka of Kyoto University in Japan reported that upregulating just four genes can apparently turn mouse skin cells into cells that closely resemble ES cells.

    Yamanaka and his colleagues hypothesized that the factors that give ES cells their unique properties might also be able to reprogram adult cells to behave like ES cells. They identified 24 genes that are specifically expressed in mouse ES cells. Six of them are well known to ES cell researchers, but the team also fingered 18 genes that are less famous in the field but are consistently turned on in ES cells.

    The team used viral vectors to introduce extra copies of the 24 genes into skin cells taken from mouse tail tips. When they inserted extra copies of all 24 genes, they found that a small percentage of cells that took up the genes did indeed seem to take on characteristics of ES cells. But no single gene introduced alone was able to manage the transformation.

    Through a process of elimination, the team whittled down the candidates to a suite of just four genes that, when introduced together into the tail-tip cells, could produce colonies of ES-like cells. As Yamanaka described, three of the four factors are old friends: Oct4, Sox2, and c-Myc are all key genes in both early embryos and ES cells. The fourth is one of the 18 lesser known genes the team had identified. Yamanaka did not name it but said it is a transcription factor that until now has not been recognized as playing a major role in ES cells.

    Reprogramming feat?

    Researchers say they have found four genes that can convert cells from a mouse tail tip into cells resembling ES cells, which are usually derived from mouse embryos such as that pictured here.


    The ES-like cells the group produced with the four introduced genes seemed to have almost all the key properties of ES cells derived from embryos. They formed several kinds of tissue in the culture dish, formed tumors called teratomas when they were injected under the skin of immune-compromised mice, and seemed to contribute to almost all tissues when they were mixed with mouse embryos and allowed to develop—all classic characteristics of ES cells.

    Yamanaka says his group has not yet tried the technique with human cells. Because of differences in human and mouse embryo development, he says, it's possible that a different set of genes would be required to reprogram human cells.

    Other researchers at the meeting were impressed. “It's huge,” says Kevin Eggan of Harvard University, who also works on reprogramming. He notes that the process is not yet very efficient; the four introduced genes managed to reprogram just 1 out of 1000 cells that received them. That suggests that the four genes are perhaps not the whole story, and that another factor could improve the efficiency of the process. “But this is the litmus test” for finding the genes that are essential for reprogramming, he says.

    • * International Society for Stem Cell Research 4th Annual Meeting, 29 June-1 July, Toronto, Canada.


    BioShield Is Slow to Build U.S. Defenses Against Bioweapons

    1. Jocelyn Kaiser

    Developing vaccines against potential bioweapons such as smallpox and Marburg virus is tough going for small companies. But it's even harder when their comrade-in-arms on the front lines, a $5.6 billion federal program called BioShield, is AWOL.

    AlphaVax, a North Carolina biotech, has already received $26 million from the National Institutes of Health (NIH) to explore how its technology, which uses a genetically modified alphavirus to stimulate a broad immune cell response against chosen microbes, can be turned into vaccines against various biothreats. But if an initial clinical trial of its prototype botulinum toxin vaccine goes well, it will likely need $100 million or more for larger clinical trials and scale-up—money that the 70-person company doesn't have on hand.

    Enter BioShield. When President George W. Bush proposed the procurement program in his 2003 State of the Union address, he reasoned that the promise of lucrative sales to the government would allow companies to keep their scientists employed and their manufacturing plants rolling. But things haven't worked that way. Companies often need more than NIH funding to be ready to bid for a BioShield contract, and even companies that succeed are paid only after they deliver a vaccine or therapy.

    Thin shield?

    BioShield has spent more than half of its money to date on a single contract for an rPA anthrax vaccine.


    Those twin “valleys of death” aren't the only flaws in BioShield, which critics say is understaffed and badly managed. The six contracts awarded to date, for $1.7 billion, are aimed at countermeasures against just three threats, and in most cases the amounts are modest (see table). Both houses of Congress are weighing legislation aimed at correcting BioShield's apparent flaws. But those potential remedies offer scant immediate hope to AlphaVax CEO Peter Young. “We don't know if there's a next step” for the 8-year-old company's biodefense products, he frets.

    Inside the black box

    Drug development is a dodgy proposition at best. But developing biodefense countermeasures is even more of a crapshoot because there's no certainty they'll ever be used. Having the government as a customer is essential, say companies. The 10-year Project BioShield created by Congress in 2004 is meant to build on the now-$1.7-billion-a-year investment in basic biodefense research by NIH's National Institute of Allergy and Infectious Diseases (NIAID).

    Getting a BioShield contract isn't simple. The bioagent for which a company is seeking a countermeasure must be on the Department of Homeland Security's list of public health “material threats.” The company must promise that the product will be available “in sufficient quantities” within 8 years. And the firm doesn't get paid until the product is delivered.

    Even before Congress created BioShield in 2004, experts warned that big drug companies would turn up their noses because the potential profits would be minuscule compared to those from, say, a blockbuster drug for lowering cholesterol. And indeed, small biotech companies have been much more likely to chase after BioShield contracts.

    But biotechs often struggle to attract the investor funding needed to get a product ready for BioShield. NIH funding rarely covers all the preclinical studies necessary to qualify, says Robert Housman, a homeland security consultant in Washington, D.C. And scaling up manufacturing and conducting later-stage clinical studies of a typical drug or vaccine costs “at least $100 [million] to $150 million,” he says. NIAID has helped fund those steps for two products: new smallpox and anthrax vaccines. But an institute official says that regularly paying for development could devastate NIAID's budget.

    Those practices have put some companies in a holding pattern. “We have been frustrated by the limitations of the current system,” Bruce Cohen, CEO of Cellerant Therapeutics Inc., told a House panel in April. Cellerant has used NIAID funds to collect promising animal data on a cell-based treatment for restoring the immune systems of victims of radiological attack, he says, but the company needs another $10 million to $20 million for scale-up and clinical trials.

    Even if a company manages to cover development costs, a sale to the Department of Health and Human Services (HHS), which awards BioShield funds, is hardly a shoo-in. “The system is not transparent, and the government doesn't tell you what it wants,” says Francesca Cook, vice president of policy and government affairs at PharmAthene, an Annapolis, Maryland-based biotech that has been waiting a year for HHS to request new proposals for antianthrax antibodies. In contrast, Cook says, the Defense Department has been much more open about its interest in the company's nerve agent treatment.

    Critics lay part of the blame on HHS's Office of Public Health Emergency Preparedness, which manages BioShield. Tara O'Toole, director of the University of Pittsburgh Center for Biosecurity in Pennsylvania, estimates that the 50-person office needs to triple its size and employ more experienced hands. Many potential bioweapons, such as Marburg virus, are missing from BioShield's current eligibility list, and it's not clear if or when they will be added.

    BioShield has struggled to manage existing contracts, too. The most notorious case involves VaxGen, which in 2004 received an $878 million contract to supply recombinant anthrax vaccine. The company had to reformulate its vaccine after learning that its active ingredient had a short shelf life. But company officials say the government moved the goalposts this spring by asking for additional clinical and animal tests and insisting that VaxGen should pay for the extra work, which has pushed back the 2006 delivery date by 2 years.

    “Contemplating that interaction doesn't whet industry's appetite” for working with the government, says AlphaVax's Young. Neither does the fact that HHS may order less of a product than a company expects. For instance, last month HHS contracted with Human Genome Sciences Inc. in Rockville, Maryland, for just 20,000 doses of an anthrax treatment rather than the possible 100,000 mentioned in an earlier agreement.

    Corrective action

    Congress has begun to address some of these concerns. In December, legislators agreed to insure companies against liability for vaccines, a major omission in the original legislation.

    Building on a measure passed last year by the Senate Health, Education, Labor, and Pensions Committee, Senator Richard Burr (R-NC) has called for a new Biomedical Advanced Research and Development Agency (BARDA) that would serve as a “single point of authority” within HHS for developing countermeasures for biodefense and natural pandemics. BARDA would bridge the valley of death by spending up to $500 million of BioShield for “advanced development.” Burr's bill, S. 2564, would also allow BioShield payments for manufacturing and for achieving certain milestones, permit the HHS secretary to hire contractors at salaries exceeding federal levels, and set up an advisory board, with members from industry, to identify new biological threats. The bill also tones down controversial exemptions to open-records laws in the previous version, although some of these provisions remain.


    BioShield is supposed to help U.S. officials respond better to incidents such as the anthrax-laced letters mailed to legislators in 2001.


    A companion bill in the House, introduced by Representative Mike Rogers (R-MI) last month, would provide $1.07 billion over 3 years for BARDA. A Senate staffer says that the money would come from shifting $160 million now tagged for advanced bioweapon product development in NIH's 2007 budget and other funds already appropriated to combat pandemic flu. The staffer says the Bush Administration requested the reallocation.

    HHS officials say they are “quite supportive of the intention” of both the Burr and Rogers bills and are already working on a strategic plan that the legislators have proposed. But observers say a bigger pot is needed, too. The Alliance for Biosecurity, a collaboration of companies and O'Toole's center, cites a 2000 Defense Science Board study that identifies at least 19 major biothreats and notes that developing a drug or vaccine costs $800 million. “The government has not recognized the reality and the scale of the biodefense threat,” says O'Toole. Still, she calls Burr's bill “a milestone in this evolving and emerging discussion.”


    A Mixed Bag of U.K. Open-Access Plans

    1. Eliot Marshall

    CAMBRIDGE, U.K.—The open-access movement chalked up a victory in Britain last week, but it did not get the universal mandate for free release of research papers that some advocates want. In a long-delayed policy statement on 28 June, the executive board of Research Councils U.K. (RCUK), an umbrella organization for government funding bodies, said that all peer-reviewed journal papers produced by publicly funded research must be made available for free soon after they're completed. Exactly what that means was not specified, and RCUK left each research council to set its own rules. In coordinated announcements, some set out hard-edged policies whereas others said they were still debating what to do.

    The most stringent policy came from the Medical Research Council (MRC), source of roughly $400 million in annual biomedical grants. It declared that any papers accepted by a peer-reviewed journal must be deposited “at the earliest opportunity—certainly within 6 months—in PubMed Central,” the free public archive run by the U.S. National Library of Medicine. A mirror U.K. archive is under construction, MRC says, and when it is ready all MRC-funded papers will go there. The rule applies to grants awarded from October 2006 onward, and an MRC spokesperson explains that the 6-month clock begins to run from a paper's publication date.

    The Biotechnology and Biological Sciences Research Council, which backs more applied projects, took a softer line. It stipulated that papers should be submitted only “at the earliest opportunity” and placed in “an appropriate e-print repository.” Other statements were even less precise. The Engineering and Physical Sciences Research Council, for example, said that “the issues are complex” and must be examined further; the council will await the results of a study due in 2008. The Particle Physics and Astronomy Research Council said merely that it “will consider … what changes might now need to be made.”

    The news that MRC is setting hard deadlines won praise from some advocates of open access, such as BioMed Central, a London-based commercial scientific publisher funded by billing authors rather than readers. “It was a very important step,” says publisher Matthew Cockerill. “Not many other funding institutions have gone as far.” MRC is following the lead of the largest U.K. research charity, the Wellcome Trust, which spends $890 million per year on biomedicine. Last year, Wellcome told all grantees they must submit accepted research papers to PubMed Central so that they could be released “no later than” 6 months after official publication. According to Cockerill, MRC's decision means that nearly all new biomedical papers in Britain will come under open-access rules. In the United States, meanwhile, Congress is considering a bill that would require papers funded by the National Institutes of Health be placed in PubMed Central within 12 months of publication (Science, 16 June, p. 1585).

    Cockerill was also encouraged by a sentence in the MRC announcement indicating that the government may pay the costs of publishing in open-access journals. (The Wellcome Trust already reimburses authors.) But others worry that the costs of moving to open access are growing. BioMed Central charges between $1380 and $1750 per article; Cockerill reports that at these rates, it is “almost breaking even.” The U.S.-based Public Library of Science, which is subsidized by foundation grants, recently raised its maximum fee from $1500 to $2500 per article. And an experimental open-access journal launched in June by the Royal Society in London, EXiS Open Choice, is planning to charge $415 to $553 per printed page. No-subscription publishing can be very expensive, says London-based consultant Mary Waltham, “and many publishers were disappointed” last week to see that RCUK did not back its open-access policy with a promise of new financial support.

    RCUK recognizes that it is moving into unexplored territory. To investigate the costs and risks, it is recruiting three major companies (Macmillan, Elsevier, and Blackwell) to join in a 2-year analysis of the impact of mandating free release of journal articles. It will review these policies in 2008.


    Across a Political Divide, Researchers Converge on Himalayan Plan

    1. Pallava Bagla

    DEHRA DUN, INDIA—A few dozen geoscientists met here in the foothills of the Himalayas last week to lay the groundwork for a bold initiative that would bring researchers from India and Pakistan together on joint projects in Kashmir. But there was a glaring hitch: Their Pakistani colleagues were on the other side of the border.

    It wasn't supposed to be like this. After months of delicate planning, scientists had been set to gather in Islamabad at the end of May to hammer out a research plan for the western Himalayas, in particular the Karakoram Mountains. “There can't be a better natural earth science laboratory than the high Himalayas,” says John “Jack” H. Shroder, a geoscientist at the University of Nebraska, Omaha, and co-organizer of the meeting, funded in part by the U.S. National Science Foundation (NSF). A centerpiece was to have been a discussion of a “science peace park” centered on the Siachen Glacier, a high-altitude graveyard for troops on the disputed border.

    A world apart.

    Tensions between India and Pakistan are hampering plans for geophysics research in the western Himalayas, including the iconic Siachen glacier.


    At the last minute, however, the Pakistan government withdrew its support for the meeting, citing security concerns (Science, 26 May, p. 1117). The cancellation appeared to be collateral damage from the glacial pace of India-Pakistan talks on Siachen demilitarization, says Harry Barnes, a former U.S. ambassador to India who is advising NSF on the initiative.

    Event organizers regrouped as best they could. On 31 May, 35 Pakistani and six U.S. scientists met in Islamabad to cobble together a research manifesto for the western Himalayas. A similar wish list was produced in Dehra Dun by a few dozen Indian scientists and colleagues from Canada and the United States. Neither meeting had local government support; Pakistan denied visas to Indian scientists, whereas Dehra Dun organizers say that time was too short after the May debacle to seek visas for Pakistani counterparts.

    A top priority of all sides is to better understand Himalayan geodynamics. Accentuating the need for such studies is the earthquake that struck Kashmir on 8 October 2005, killing more than 100,000 people. The magnitude-7.6 quake “was a wake-up call … that temblors do not respect national boundaries,” says Shroder. One nasty surprise was that the quake's epicenter—the Muzaffarabad fault—was not known to be active, he says.

    Researchers called for the installation of a seismic network to better map tectonic activity in the western Himalayas. That would require unprecedented cooperation between Indian and Pakistani security forces, says Michael P. Bishop, a geoscientist at the University of Nebraska, Omaha. Researchers also hope to undertake active seismic profiling, in which explosives are detonated in deep holes. The vibrations reveal rock composition and fault structure—vital to refining maps of seismic risk. Mary Leech, a geologist at San Francisco State University in California, has tried to launch such work with Indian colleagues. “We have been stopped because of the complex political problems,” she says. “Carrying out even small explosions in border areas can be very problematic.”

    Both meetings generated other ideas under the banner of a “Siachen Science Laboratory.” Proposals include probing the potential effects of climate change on monsoons and documenting the retreat of border glaciers. Barring a rapprochement on the Siachen military issue, the scientists intend to meet next year in a neutral venue—possibly in the Italian Alps—to merge research agendas and seek sponsors.

    Although the absence of Pakistani researchers was acutely felt in Dehra Dun, Shroder urged scientists to keep their spirits up. “Just keep pushing the edges, and little by little, good science can be done,” he said. And as Baldev R. Arora, director of the Wadia Institute of Himalayan Geology in Dehra Dun, optimistically predicted, “Opportunities for collaborative work among all Himalayan neighbors can only increase.” It may take a significant thaw between cold warriors for those hopes to become reality.

  7. JAPAN

    Top Chemist Accused of Funds Misuse

    1. Dennis Normile

    TOKYO—One of Japan's most prominent scientists is facing allegations of misappropriating funds. Kazuko Matsumoto, who was poised to become head of an international scientific society, has acknowledged improperly handling payment requests but claims the money was used for research purposes. The case has prompted government officials to call for stricter oversight of research grants.

    Probe target.

    Kazuko Matsumoto.


    Tipped off by a whistleblower, Waseda University in Tokyo last April launched an investigation into the financial dealings of Matsumoto, 56, a chemist in the university's School of Science and Engineering. In a 5-page interim report released on 23 June, the investigating committee said that between 1999 and 2003, Matsumoto drew $128,000 from publicly funded research grants to pay wages of six students she claimed were working part-time in her lab. According to the report, the students had not worked for Matsumoto, and the money was channeled into a personal bank account. She later transferred $78,000 into a personal investment fund managed by a stock brokerage and spent another $10,000, the report states.

    The report says Matsumoto admitted improperly handling the student payment requests but said the money was used for student travel expenses and to purchase supplies. It notes that she has agreed to return the money. The report also alleges that Matsumoto may have made more than $200,000 worth of fictitious purchases from a biotechnology firm she was working for as a part-time director, but the committee acknowledges it lacks conclusive evidence and that Matsumoto has denied any wrongdoing. The probe is continuing.

    Matsumoto declined to comment. “When the time comes, I might have something to say, but right now I am not saying anything to the media,” she told Science.

    The allegations have dealt a severe blow to Matsumoto's career. A few days after the report's release, she resigned as vice-president of the International Union of Pure and Applied Chemistry (IUPAC). She was due to ascend to the presidency in January 2008, when she would have been the first female president in the society's 87-year history. “We're sorry this happened to her,” says John Jost, IUPAC executive director. The society's governing body will decide what to do about the vacant post when it meets this fall.

    From 2002 until last January, Matsumoto was a member of the Council for Science and Technology Policy, Japan's highest science advisory group. She had also served on a Ministry of Education committee on research misconduct.

    The committee's report leaves a number of questions unresolved. It notes, for example, that a separate Waseda panel is investigating allegations that data were fabricated in a paper that Matsumoto wrote with a collaborator. The report also declares that officials in the School of Science and Engineering had learned of concerns about Matsumoto's handling of funds 2 years ago but hadn't followed up. Waseda President Katsuhiko Shirai is heading a new panel to create procedures for preventing the misuse of research funds.

    Government officials have been roused to action. Referring to the Matsumoto case on 29 June, Iwao Matsuda, minister for Science and Technology Policy, promised to have guidelines on preventing abuse of research funds drawn up this summer. If organizations don't fall in line, he stated, “we will withhold their competitive grants and take other measures.”


    After the Tsunami: A Scientist's Dilemma

    1. Richard Stone

    Simron Singh had earned a reputation as a top expert on the Nicobarese. Then disaster struck, and Singh made a fateful decision: to ditch any pretense of objectivity and help rebuild their culture and their lives


    BANGKOK—Two days after a massive tsunami pummeled southern Asia in December 2004, a message picked up by shipboard radio reached Simron Jit Singh at his parents' home in Lucknow, India. It was from Rasheed Yusuf, a close friend in the Nicobar Islands, a little-known archipelago a few hundred kilometers from the earthquake that triggered the tsunami. The news was bad: “Central Nicobars entirely washed out. … Do something as soon as possible.”

    Singh, a human ecologist and anthropologist at the Institute of Social Ecology in Vienna, had spent the previous 5 years chronicling the indigenous Nicobarese. He lived among them for weeks at a stretch, earning their trust and gathering a wealth of information. Now the society itself seemed to be slipping away: Out of a population of 30,000, about 4500 had perished in the tsunami; another 5000 were missing and presumed dead. Nine of every 10 homes on the 24-island chain were reduced to splinters. The islanders' economic lifeblood, coconut palms, was virtually wiped out. Most insidious, nearly every artifact—irreplaceable ossuaries and other relics preserved for generations—had been washed away.

    The tsunami left the numbed survivors at a crossroads. Leaders were torn between either trying to restore their cultural identity or accelerating a fitful integration with the outside world in which many Nicobarese had already adopted Western clothing and other trappings of modern life, from television to pop music. Tribal elders sought the counsel of an outsider they knew they could trust: Singh.

    That left Singh facing his own moment of truth. Until then, he had remained loyal to the scientific creed of minimal intervention. Yes, many research subjects had become friends and confidants. And yes, his work was influencing their lives in subtle ways. Now, however, the Nicobarese were asking Singh for much more: to cross the line between observer and participant and help make decisions that could determine whether the islanders would retain centuries-old traditions as a facet of their rapidly changing lifestyle.

    It didn't take Singh long to decide. He flew to the Nicobars in late January 2005 and, since then, has assisted the islanders in restoring their culture and reshaping their economy. “He has literally single-handedly brought to the world's attention the cultural, social, and economic plight of the Nicobarese,” says Mahendra Shah, a sustainable-development expert at the International Institute for Applied Systems Analysis (IIASA) in Vienna. Shah and others applaud the path Singh chose. “He could not in good conscience do anything else,” says Pernille Gooch, a human ecologist at Lund University in Sweden.

    Singh had looked into his heart and knew, he says, that “I really had no choice.”

    Listening and learning

    Singh, 36, became involved with the Nicobars by chance. His first project as a student at Lund in the mid-1990s had been a study of the Van Gujjars, a tribe of nomadic buffalo herders in the Himalayas. Then one day in 1998, an Indian historian tracked him down at a Van Gujjars camp and urged him to study the Nicobarese. He was intrigued.

    Working in this remote community, Singh learned, would not be easy. Many Nicobarese view outsiders with suspicion—for good reason. They have been host to a series of unwanted visitors. Situated on the trade routes between India and East Asia, the archipelago was colonized by Denmark in 1756, then by Austria, and finally by Great Britain, which held the Nicobars until India's independence in 1947; they are now formally part of India. But it remained a “marginalized society that few people had heard about,” says Gooch.

    To protect the indigenous peoples of the Nicobar Islands, as well as those on the Andamans to the north, India places strict controls on outsiders' access. Singh has Indian nationality, which helped him get a research permit, but he had to promise not to divulge any information deemed sensitive to Indian security. Yet his nationality was also a liability: The Nicobarese are wary of Indian traders on the islands. What's more, tribal elders held scientists in low esteem. When Singh visited in April 1999, the first impression of Ayesha Majid, chief of Nancowry Island, was “that he was just like other people who come, hear, write, and leave.” Singh spent 2 months on nearby Trinket Island and promised to come back. “We were rather sure that he wouldn't,” Majid says.

    Culture shock.

    A young man tests his mettle against a tethered pig in a festival on Chowra Island in 2001 (above). The same spot, viewed from a different angle, is shown here after the 2004 tsunami.


    Singh's return dumbfounded the Nicobarese. “After nearly a year, we see Simron walking towards my home with a black bag on his back and a smile on his face,” Majid says. “His respectful behavior touched us all.” She says he would partake in raw fish and pork with the islanders, observe ceremonies even in the dead of night, and quiz them “endlessly” about their culture and traditions.

    Fond farewell.

    Simron Singh (far left) receives a traditional sendoff—a smearing of coconut oil on his forearm and a garland of banana leaves—from a Nicobarese leader in Pilpillow village on Kamorta Island last April.


    Singh kept returning, season after season, fascinated by a “very rich” culture preserved by limited contact with outsiders on some of the islands. He witnessed unique traditions, such as the annual pig festival, Panuohonot, which features a coming-of-age rite in which young men prove their valor in hand-to-hoof combat with pigs, and an ossuary celebration, Kinruaka, in which ancestral bones are dug up and reburied. Singh learned how heavily the Nicobarese depended on coconuts. A third of production was reserved for raising pigs, which grew extra-fat on the oil-rich diet. “To be a Nicobarese means to have pigs. The more pigs you have, the better off you are,” Yusuf says.

    For his thesis at Lund University, Singh explored the social metabolism of Trinket, unraveling the island's life in a monograph, In the Sea of Influence. “It's a thorough political, economic, and environmental history of these forgotten islands,” says Joan Martínez-Alier, president of the International Society for Ecological Economics and a professor at the Universitat Autònoma de Barcelona in Spain.

    The more Singh got to know the islanders, however, the more he worried about their future. Long before the tsunami, he decided they needed better links to the outside. Tensions between Nicobarese and ethnic Indians over land use and trade were likely to worsen over time, he felt. And the one-dimensional coconut economy made the Nicobarese “very, very vulnerable,” says Yusuf. “We needed an alternative economy.”

    Singh concluded that the more information the Nicobarese had, the better armed they would be to make decisions about their future. He helped arrange invitations from Vienna and Lund for Yusuf to visit Europe. The trips were eye-opening, says Yusuf, who was one of the first Nicobarese to visit a foreign land and now handles external affairs for the tribe.

    Privately, Singh had reservations about his evolving relationship with the Nicobarese. With his supervisor, Marina Fischer-Kowalski, director of the Institute of Social Ecology, he discussed whether he should wrap up his research in the Nicobars and move on. “Many things I was doing, I wouldn't tell my colleagues,” Singh says. “It was bad. I was intervening.”

    Wolfgang Lutz, an IIASA demographer and leader of IIASA's World Population Program, recalls Singh's quandary. “I remember well discussing with him in 2004 whether this unique culture … should be left entirely alone or whether there is a case for introducing some of the usual development measures such as health care and education,” Lutz says. “It was evident from the past experience of many other populations that even the most ‘benign’ interventions, such as helping to reduce child mortality, in the long run will change the living conditions and therefore also the culture,” he says. “My personal preference as a scientist was to restrict our role mostly to observation.”

    The tsunami, Lutz acknowledges, “made such considerations obsolete.”

    Cultural annihilation

    When the magnitude-9.0 earthquake jolted the Nicobars in the early morning of 26 December 2004, Yusuf was among a group on Nancowry Island who retreated to the beach to keep clear of buildings in case of aftershocks. That's when he says he noticed the sea receding. “I told people to run. There was a hill nearby,” Yusuf says. Thanks to Nancowry's favorable geography—it has high ground, and other islands shielded it from the full brunt of the waves—just one person on Nancowry died in the tsunami.

    Other islands in the chain were not as fortunate. Some are so low that the waves washed right over them. Trinket, the site of Singh's in-depth study, was carved into three islets. The chief of the tribal council requested Fischer-Kowalski to allow Singh to travel to the Nicobars immediately and stay for a few months. “In this situation, it had little to do with scientific roles but was rather a matter of human reciprocity,” Fischer-Kowalski says. Other colleagues preached caution. “We told him, ‘The tragedy is too large; you are only one young expatriate academic with not much influence in India,’” says Martínez-Alier. “We also said, ‘Think of yourself.’ He did not.”

    When Singh arrived at the end of January 2005, he was confronted with utter devastation. Most survivors were living under tarpaulin shelters. And their cultural heritage had been obliterated. All but two kareau, carved wooden effigies bearing ancestral bones, were gone. “We can bring back pigs,” Yusuf says. “But the bones are lost.”

    To the rescue

    Back in Vienna, Fischer-Kowalski was rallying institutional support. Klagenfurt University, which oversees her institute, spearheaded a fundraising drive for reconstruction. Under the auspices of Caritas Austria, a Catholic relief agency, and Universal Music Group, which donated the proceeds from sales of a CD recorded to support tsunami victims, the university set up the Sustainable Indigenous Futures (SIF) Fund to support self-rehabilitation efforts of indigenous peoples affected by the tsunami. And the Austrian Science Fund stepped up to bankroll a scientific assessment of sustainable development in the Nicobars.

    Many colleagues applaud Singh for taking on these responsibilities. “As I see it now, there is no dilemma left for the scientist at this point,” says Lutz. Singh, he says, is “bringing the best scientific information available to the attention of the local decision-makers” as they plan for reconstruction of homes and other infrastructure. “Disasters happen daily to some of the peoples we study,” adds Martínez-Alier. “I ask myself why it does not happen more often that social scientists turn into advocates.”

    Last September, Singh's institute and the SIF Fund hosted six Nicobarese tribal leaders. Colleagues took them to Austrian villages rebuilt after the disastrous floods of 2003. “These were villages with 900 years of history,” says Singh. “We wanted to show them that no matter how difficult the ordeal, you don't ever have to give up your culture.”

    To help reconstitute the islands' cultural heritage, Singh is drawing on an extraordinary resource. The Museum of Ethnology Vienna has more than 200 Nicobarese artifacts collected in the 19th century—in the wake of the tsunami, one of the largest collections in the world. Some objects will be lent to the Nicobarese and copies of others manufactured. “These remind us of our way of life and will help us preserve it,” Yusuf says.

    Other momentous changes are on the horizon. The Indian government, pending approval from the defense establishment, may open the Nicobars to expanded trade and tourism. The Nicobarese “aren't saying they want to live like museum pieces,” Singh says. But they don't want to lose their identity by integrating fully with the outside world. “What Simron is doing that's so special,” says Brian Durrans, deputy keeper in the British Museum's Asia Department, “is a combination of refusing a patronizing ‘isolationist’ option while encouraging the Nicobarese to become their own advocates. It's a pretty inspiring approach in conditions of sudden catastrophe.”

    Exposed to new ideas—and the elements.

    Nicobarese children in a makeshift school at a relief camp on Kamorta Island.


    Singh is also advising the Nicobarese on how to diversify their economy, which had been based almost entirely on swapping or selling coconuts and coconut products for goods from ethnic Indians. Before the tsunami, Singh says, the Nicobarese were “not prepared” to shift away from a reliance on coconuts. Now they understand that it will take years to restore the palm groves. In the meantime, they expect to derive income from fishing and garden plots.

    All the more valuable.

    One of only two kareau, effigies bearing ancestral bones, that was not swept away by the tsunami.


    Singh, who returned to Vienna in May after a 2-month stint in the Nicobars, says the latest challenge is helping the islanders learn the value of money. Recently, each family received cash compensation from the Indian government. The money has been burning a hole through the tribal pocket, as islanders pay two or three times the going rate for everything from motorcycles to DVD players. “The accumulation of capital is rare, if not unknown,” Singh says. “It's the major problem at the moment.”

    The jarring transitions have driven many young Nicobarese in search of a better life to Port Blair, the relatively developed capital of the Andaman Islands. “I fear that the younger generation might turn their backs on us,” Yusuf says. Samir Acharya, president of the Society for Andaman and Nicobar Ecology in Port Blair, believes a mass exodus is unlikely. He says that conversations with a few dozen young Nicobarese in Port Blair suggest they are “all likely to go back to their respective villages.” Nevertheless, most experts agree that the Nicobarese culture is hanging by a thread. The situation, says Gooch, “is really grim.”

    Now Singh has reached another crossroads. At the moment, he does not know whether to return to the role of detached observer, turn toward advising the Indian authorities, or continue with reconstruction projects. Singh's colleagues are confident he will choose a noble path. “He'll do the right thing,” says Gooch—as a scientist and as an advocate.


    Isolate or Engage? Indigenous Islanders Pose Challenge for India

    1. Pallava Bagla

    NEW DELHI—Three hours by air from this metropolis are a few societies of ancient lineage: the Nicobarese (see main text) and five other indigenous tribes of the Andaman and Nicobar islands, two of which still pursue a hunter-gatherer lifestyle. The Indian government is grappling with how best to protect these fragile cultures: whether to sharply limit their contact with outsiders or slowly integrate them into modern society.

    “The approach we take does not promote complete isolation nor does it advocate complete integration, but a middle ground,” says V. R. Rao, director of the Anthropological Survey of India in Kolkata. “Any policy on the Andaman aboriginal groups should allow them a large measure of independence in choosing their own future,” adds Sita Venkateswar, a social anthropologist at Massey University in Palmerston, New Zealand, who has studied one tribe, the Onge, for several years.

    Remembrance of genes past.

    Like others of their tribe, this Great Andamanese family has assimilated into modern society.


    Indeed, the tribes themselves are largely setting the pace of integration. At one extreme is the Sentinelese of tiny North Sentinel Island in the Andamans. This group, estimated at 100 individuals, may be the last culture in the world maintaining a Stone Age lifestyle, according to the Tribal Welfare Department of the Andaman and Nicobar Administration (ANA). Contacts are virtually nil. “We know about wild tiger numbers in India but don't know the exact population of the Sentinelese,” says Vishvajit Pandya, an anthropologist at the Dhirubhai Ambani Institute for Information and Communication Technology in Gandhinagar, who has studied the Onge and the Jarawa.

    The Sentinelese prefer isolation. A friendly contact occurred 15 years ago, when an ANA team sailed to the island bearing gifts of cloth, coconuts, and bananas. But that overture was criticized by civil society groups on grounds that the tribe, which had not sought contact, should be left alone to prevent risks such as introduced diseases.

    Since 1991, ANA has enforced a hands-off policy toward the Sentinelese. The only exception was a mission to check on how they fared in the 2004 tsunami. When an Indian Air Force helicopter flew over the island, it was greeted with a barrage of arrows and turned back. Then last January, two fishers entered the waters of North Sentinel Island, reportedly to poach crabs. They were allegedly slain and buried in the sand, says Samir Acharya, president of the Society for Andaman and Nicobar Ecology in Port Blair, the Andaman capital. Police exercised restraint by not pressing charges or venturing into Sentinelese territory to retrieve the bodies, Acharya says.

    But other tribes are reaching out. The Jarawa, once hostile like the Sentinelese, began to visit ethnic Indian communities in 1998, sometimes seeking medical assistance. Their benign forays pose a challenge for the government: Heightened contact may erode tribal culture, whereas a hands-off approach would be difficult to sustain and justify, particularly when medical aid is sought. The government has since established a health outpost bordering Jarawa settlements.

    Prodded by Indian courts, ANA in December 2004 declared the Jarawa reserve “inviolate” and set measures to protect it from further encroachment. Human-rights and environmental groups are not satisfied, however, and petitioned the Supreme Court to force the government to cocoon the Jarawa and other tribes from the outside world; a verdict is expected soon. “On paper, India's policy is … one of the most advanced on isolated peoples anywhere in the world,” says Stephen Corry, director of Survival International, a London-based nonprofit organization that promotes the welfare of indigenous peoples and is not involved in the legal action. However, he contends, if authorities do not stiffen enforcement of a no-go zone around Jarawa land, “the Jarawa will not survive.”

    The other four Andaman and Nicobar tribes—the Onge, Great Andamanese, Shompen, and Nicobarese—are all assimilating into modern society. Last year, a mitochondrial DNA study of Great Andamanese and Onge individuals in Science suggested that these peoples could be the oldest surviving human stock in Asia (Science, 13 May 2005, p. 996). The tribes are “a gold mine of ancient, undiluted genetic information,” says Lalji Singh of the Centre for Cellular and Molecular Biology in Hyderabad, who led the work. But these living links with humanity's past are fraying. The Great Andamanese, who are said to have been 10,000 strong at the end of the 18th century, are down to 20 individuals, and the Onge number only 98.


    Keeping the Bugs at Bay

    1. Kevin Krajick*
    1. Kevin Krajick is a New York City-based writer who is unattractive to bugs.

    Public health money gives a boost to the untidy science of crafting a better insect repellent

    Following their noses.

    USDA's Don Barnard works with a chamber that allows mosquitoes to follow or avoid certain smells.


    Andrew Fowles, a high-school security guard in Davis, California, is a part-time grunt in the war on biting insects. For $30 an hour, he has served as a test subject from Sacramento to the Florida Keys, dousing himself with experimental bug repellents, then thrusting an arm into a mosquito-filled cage or marching barelegged through bug-swarmed wetlands. He once got about 1500 mosquito bites on his calf—two bites per second. “I'm not squeamish. I like to contribute to society,” he says.


    Bug-repellent research, long waged on primitive levels and with mixed results, may be looking up. The developed world once viewed repellents chiefly as products for backyard comfort, but with the spread of insect-borne agents such as West Nile virus, they have become a public-health issue. There is also growing recognition that vector-borne diseases routinely devastate the developing world; in Africa alone, 800,000 children die from malaria every year. Expensive research into vaccines, medicines, and genetic modifications to wild insects has so far delivered little, so many scientists are going back to basics: insecticides, bed netting, and repellents.

    Free lunch.

    Mosquitoes gorge themselves on an artificial food source in the lab.


    With new funding initiatives, biologists are using more sophisticated methods to improve understanding of insects' finely evolved olfactory systems and to find substances that might disrupt them. Researchers have uncovered possible new repellents in nature and in the lab, and a few have already made it to market; others may be on the way. “If we can really understand how insects find us, we can figure out how to prevent them from finding us,” says Yale University molecular neurobiologist John Carlson, part of a new three-continent team.


    Trying to beat DEET

    Cultures from ancient Egyptians to modern U.S. Southerners have used remedies as diverse as snakeskin and cow parsnip to keep away pests. But so far the Holy Grail—a compound that bugs hate and humans find pleasant—has been elusive. The central weapon in the modern arsenal is N,N-diethyl-meta-toluamide, or DEET; invented in 1953, it smells evil, melts plastic, and is perceived by many people to be poisonous. No one even quite knows how it works. At 30% concentrations, DEET drives away a broad spectrum of bugs for up to 8 hours, including Culex pipiens mosquitoes, which carry West Nile virus. However, many commercial products carry as little as 7% DEET because it's so unpleasant, and even high concentrations fall short against Anopheles mosquitoes, which spread malaria, and against ticks, which spread Lyme disease and Rocky Mountain spotted fever. The U.S. military has found that in the fierce heat of Iraq, DEET evaporates quickly. In the current war, biting sandflies have inflicted close to 2000 cases of leishmaniasis, which causes debilitating skin lesions.

    Psychology also plays a role. The U.S. Department of Defense recently revived work on new repellents after finding that soldiers often toss out green tubes of military-issue DEET because they fear it is toxic and hate its sticky feel. Some unknowingly replace it with the same stuff in a more colorful package aimed at civilians, says Lt. Col. Mustapha Debboun, a medical entomologist at the Army Medical Center and School in Fort Sam Houston, Texas.

    DEET actually has a good safety record, asserts Debboun, who heads the armed forces' repellent committee and is co-editor of the forthcoming book Repellents, the first overall look at the field. The compound is used hundreds of millions of times worldwide each year, with only about 50 known reports of severe dermatitis or seizures since it came into use—problems usually attributed to gross overuse, if they can be clearly connected to the product at all. “But if soldiers are afraid of it, we need to look for alternatives,” says Debboun.

    Some researchers are turning to folk remedies—and finding a few that may work, at least to a degree. The U.S. Department of Agriculture (USDA), which has traditionally led American research at the relatively modest funding rate of about $1 million per year, has shown that many plant oils, including clove, peppermint, geranium, and catnip, may repel mosquitoes. Botanists have long known that plants produce compounds to combat pests that might eat them; entomologists speculate that there may be a chemical spillover effect on those that eat us.


    For example, last year Stoneville, Mississippi-based USDA botanist Charles Bryson showed that his grandfather was right when he shoved American beautyberry leaves under his draft animals' harnesses to repel biting flies. Bryson and colleagues reported in the Journal of Agricultural and Food Chemistry that they have isolated five compounds that repel bugs including Aedes aegypti, the mosquito species that carries yellow fever. They have patented one substance, called callicarpenal, and are looking for a commercial partner for development.

    Animals may also employ natural repellents. Recently, Paul Weldon, an animal behaviorist at the Smithsonian Institution in Washington, D.C., observed that some monkey species rub themselves with millipedes that secrete benzoquinones, compounds shown in the lab to repel insects. He reported in the journal Naturwissenschaften in January that coatis sense benzoquinones and roll millipedes around in an apparent effort to draw them out. Weldon says that many other mammals and birds anoint themselves with plants or other items, many of which show some repellent effect.

    Other creatures, from giraffes to gaurs, may produce their own repellents. Auklets on arctic islands exude aldehydes that drive off ticks and mosquitoes and kill lice in lab experiments, according to a paper last year in the Journal of Medical Entomology by ecologist Hector Douglas of the University of Alaska, Fairbanks. Repellents are not trivial for the birds; the insects are so vicious that they can threaten breeding colonies' existence. Douglas says that during buggy times, one can smell the citrusy aldehydes a kilometer away from colonies.

    But there are many obstacles between identifying natural repellents and deriving marketable products from them. A widely cited 2003 study in The New England Journal of Medicine by Chapel Hill, North Carolina, dermatologist Mark Fradin shows that many “botanicals,” including popular citronella formulations such as Avon Skin-So-Soft, work—but only for 3 to 20 minutes. Part of the problem is that the compounds are usually quite volatile and evaporate unless constantly replaced. Some natural oils will repel bugs for up to 2.5 hours, but only if they are distilled down to something near the pure stuff, which is usually stinky and toxic, says Don Barnard, a USDA entomologist in Gainesville, Florida. Aldehydes, for example, smell nice in low doses but are hard to bear once purified. High doses also may corrode people's mucous membranes and livers. “I know one lady who put 100% clove oil on her face, and she got horribly burned; she must have been pretty desperate to go organic,” says Barnard.

    All the same, researchers continue to hunt for natural repellents, including those produced by humans. Ulrich Bernier, a chemist at USDA's Agricultural Research Service in Gainesville, has identified about 275 substances in human sweat, including aldehydes similar to those produced by auklets, along with ketones, fatty acids, and ammonia. Human breath contains carbon dioxide—long known as the crudest insect attractant—but also may contain substances similar to those in sweat. Bernier says many, such as lactic acid, act as attractants at low concentrations but become repellents when distilled, combined in certain proportions with other emanations, or modified into slightly larger molecules. Everyone sweats out the same chemicals, but the concentrations and proportions may vary widely among individuals—possibly the key to why bugs eat some folks alive but leave others alone. Bernier has already patented several chemical leads derived from his research.

    On guard.

    Auklets produce natural repellents.


    One group at the United Kingdom's government-funded Rothamsted Research has combined human and animal research. Biochemist John Pickett has shown that some cattle exude powerful compounds that keep biting flies off themselves and nearby animals. The tendency to produce the substances appears to be inherited through the mother, he says. Rothamsted chemical ecologist James Logan says humans produce similar compounds; in as-yet-unpublished work, he has isolated what may be human emanations that work against Aedes aegypti mosquitoes and Scottish no-see-ums. With a new $500,000 grant from a government fund for new business enterprises, the group hopes to do field trials in South America and Africa over the next 2 years.

    Strongest weapon.

    The military issues DEET, the most widely used repellent, but not all soldiers like it.


    The discovery process is slowed, however, not only by the complexity of how aromas interact with one another, but also by the varying tastes of different insect species, strains within species, and even individual insects. Says Bernier: “We're just beginning to understand: Insects are like picky wine drinkers. They like something or not, based on very subtle combinations of qualities.” What repels a mosquito may have no effect on a chigger, so a versatile repellent may demand a chemical cocktail.

    Testing troubles

    Repellents' exact modes of operation remain mysterious, and this has also hindered research; most substances now in use were identified through fortuitous observations or laborious random trials. A few months ago, Jerome Klun, a USDA entomologist based in Beltsville, Maryland, finally showed in the Journal of Medical Entomology that vapors from DEET and some other substances function mainly by traveling to insects' olfactory receptors, as opposed to affecting the insects when they touch skin—a mechanism long suspected but never proven till now. However, Klun says it is still unclear whether the substances create an unpleasant sensation for insects, mask attractive odors, or work in some other way.

    To discover repellents without knowing why they work, one new Army initiative uses computers to identify molecules similar to existing repellents, then synthesizes and tests the compounds. In unpublished research, Army biochemist Raj K. Gupta, based at the Walter Reed Army Institute of Research in Silver Spring, Maryland, has made a sort of repellent template by identifying various electrical and structural qualities common to existing products. From this, a team has come up with at least four compounds now under investigation.

    But even if compounds prove interesting, documenting their effectiveness is often complicated. For example, a few new repellents are now on the market, but it's hard to compare them to each other, or to DEET. One substance is para-menthane-3,8-diol (PMD), commonly known as oil of lemon eucalyptus. Derived from the Australian lemon-scented gum tree and marketed in China for years, it appeared last year in the United States under the brand name Repel. In some tests, 20% PMD appears to be nearly as effective as most of the 240-some standard DEET products—perhaps better, says Scott Carroll, the University of California, Davis, entomologist who sent out Fowles to test the stuff. (Both Fowles and Carroll now swear by it.) Other studies, however, suggest that PMD is weaker than DEET. One problem is that there are 3000 species of mosquitoes alone, and most repellents work better on some than on others. But many tests using caged mosquitoes are conducted using only one or two species. And in the field, insects' tastes may vary dramatically by concentration of the repellent, time of day, temperature, humidity, individual volunteers, and insect species themselves—variables that few researchers try to control for.

    Sacrificial arm.

    Testers bravely offer their flesh to caged mosquitoes.


    Two other promising repellents are newly available in the United States: Picaridin, a synthetic derivative of pepper marketed under the name Cutter Advanced, and IR3535, a derivative of a single amino acid, β-alanine, now sold in a beefed-up version of Skin-So-Soft. However, research on them suffers similar complications. “What's best? It sounds like a simple question, but there really is no easy answer,” says Robert Novak, a medical entomologist at the Illinois Natural History Survey.

    Plant power.

    Many plants produce substances to drive insects away, including (clockwise from lower left) peppermint, geranium, and American beautyberry.


    Testers face another hurdle: With the spread of West Nile and other diseases to new regions, field tests against wild insects may expose human volunteers to infection. Researchers are getting creative. Instead of letting volunteers get bitten, USDA scientists now trail them through the buggy Florida Everglades with portable aspirators to suck off any mosquitoes that land and probe; most insects carry through with feeding once they start this sequence, so these events are counted as bites. For lab work, Klun and Debboun have invented the so-called K&D module: a plastic box with multiple mosquito-filled chambers pressed against a volunteer's thigh, which allows researchers to test out several repellents at once using lab-cultivated, disease-free mosquitoes.

    One improved system does away with the humans altogether by substituting a skinlike membrane filled with human blood, heated to human body temperature and treated with repellents. Klun says human volunteers will always be needed for final-stage field tests, but the new technology will minimize risk during the lengthy screening that usually precedes such tests.

    Perhaps the most sophisticated repellent effort, aimed at stages from basic biology to field tests to marketing, is a 5-year project begun last September and funded by the Bill and Melinda Gates Foundation. The $8.5 million budget is comparable to that of USDA and the U.S. military combined. Following their 2001 identification of the genes for the 80-some olfactory receptors used by malaria-carrying Anopheles gambiae mosquitoes, two labs in the United States have begun running tests with hundreds of substances to observe which cause receptors either to fire or become blocked. First, researchers transplant genes for the receptors into other biological systems that are faster and easier to work with than mosquitoes, such as frogs' eggs or fruit flies. Then they test whether various substances affect electrical currents flowing from the receptors, presumably an indicator of firing.

    Yale's Carlson has been working in part with compounds taken from human sweat and tested in fruit flies that express mosquito receptors. He has already sent a half-dozen candidate compounds on to the next stage: the lab of behavioral entomologist Willem Takken at the University of Wageningen in the Netherlands. Takken's job is to test the effects on mosquitoes' antennae and behavior. After again measuring whether receptors fire, this time in the mosquitoes' antennae, he employs wind-tunnel-like olfactometers, in which insects can choose to follow or avoid certain paths from which different smells emanate.

    Compounds that show promise will be sent to the Ifakara Health Research and Development Centre in Tanzania, where a greenhouselike biosphere about half the size of a football field is now under construction. Here, human volunteers will test candidate repellents against free-flying mosquitoes in a semicontrolled environment within the next year or so. Top picks will go to Gambia, where researchers will do full field tests in villages—then, hopefully, to market by 2011.

    Takken, Carlson, and Laurence J. Zwiebel of Vanderbilt University in Nashville, Tennessee, emphasize that they are looking not just for repellents but also attractants, following other research on what draws insects to their targets (Science, 4 October 2002, p. 176). They hope to develop a “push-pull” system that will employ repellents to drive mosquitoes away from people's beds or other feeding spots and attractants to draw them into insecticide-laced traps in distant parts of houses or villages. Their repellent would not be applied to skin but rather emitted from a simple device that would suffuse a room or outdoor area—a highly evolved version of the mosquito coil, which has long used various substances, although with only fair to middling effect. Takken says that because attractants and repellents seem related, and no single compound works on all bugs, the solutions are likely to be complex. He has already identified one apparently powerful new repellent that he hopes to publish next month. Zwiebel says the key will be to keep the system cheap and to use sales of repellents in richer countries to subsidize use in poorer ones. “The Third World can't afford what we spend to protect our backyard barbecue,” says Zwiebel. “But they really need repellents.”


    A Towering Physicist's Legacy Faces a Threatening Future

    1. Robert Irion

    On the centennial of Hans Bethe's birth, his successors worry that cuts in long-planned projects will discourage the next generation of brilliant minds

    ITHACA, NEW YORK—The language of astrophysics sizzles with alpha particles and gamma rays. There's a heavy dose of beta as well—Hans Bethe, that is, a giant of 20th century science, whose prowess in nuclear physics led to his fascination with combustion in deep space.

    Bethe probed astrophysics at its purest levels right up until his death last year at age 98 (Science, 8 April 2005, p. 219). At a recent meeting* here, speakers fondly recalled his influence in the region where nuclear physics and astrophysics fuse, from neutrinos to supernovae, and ordinary stars to neutron stars. They also laid out key mysteries that still tantalize scientists: How do giant stars explode and forge the elements around us? What happens when neutron stars or black holes crash? And what is the nature of the dark matter and dark energy that suffuse space?

    But as Bethe's scientific descendents marked what would have been his 100th birthday on 2 July, they worry about their ability to address such questions anytime soon. Cuts in the science program at NASA have cast a pall over missions designed to turn the cosmos into a high-precision physics laboratory. The damage to Bethe's legacy could be serious, they warn.

    “In the worst-case scenario, the young people we need may feel hopelessness,” says Saul Teukolsky, chair of the physics department at Cornell University—Bethe's academic home for 70 years. “They may not enter the field at all.”

    Bomb physics, near and far

    Astrophysics was the alpha and omega of Bethe's long career. Although his fame stems from leading the theoretical division at Los Alamos, New Mexico, during the Manhattan Project, and his tireless advocacy of arms control once World War II was over, astronomers and physicists revere him as “the guy who figured out how the sun works,” says astrophysicist Michael Turner of the University of Chicago, Illinois. “You don't need a better legacy than that.”

    Born in Strasbourg, Germany, and educated at universities in Frankfurt and Munich, the young Bethe spelled out the details of the proton-proton reaction that propels hydrogen fusion in the cores of modest stars like our sun. In the late 1930s, he was the first to describe a separate fusion cycle involving carbon, nitrogen, and oxygen atoms, which powers massive stars during their short lives. In 1967, Bethe received the Nobel Prize in physics for that work.

    A rare spark.

    Hans Bethe, shown at age 90, calculated how stars burn—including the “carbon cycle” in background.


    In the decades after World War II, Bethe's research focused on the theory of nuclear matter and atomic physics. A highlight was a calculation of a subtle shift in the energy levels of electrons in excited hydrogen atoms. That three-page paper, written on the train between New York City and Ithaca, set the stage for modern quantum electrodynamics.

    Later in life, however, two catalysts drew Bethe tirelessly back into astrophysics. The 1967 discovery of pulsars—flashing deep-space beacons that Bethe's Cornell colleague Thomas Gold explained as spinning neutron stars—sparked Bethe's intense desire to understand the properties of superdense states of matter. Drawing from his deep well of nuclear physics, Bethe and colleagues wrote papers on the internal structures of neutron stars. They derived a likely radius of 10 kilometers, a figure still in vogue.

    Soon after Bethe “retired” in 1976, his friend Gerald Brown of the State University of New York, Stony Brook, piqued his interest with a challenge to work out the nature of supernovae. The two scientists spent much of the next 3 decades pondering how giant stars blow up, their prodigious outbursts of neutrinos, and binary systems of neutron stars and black holes.

    These topics followed logically from Bethe's work on the atom bomb, says astrophysicist Stan Woosley of the University of California, Santa Cruz. “Stars are gravitationally confined thermonuclear reactors,” and their demise is bomb physics on the grandest scale, Woosley says. “And Hans was really interested in the birth of the elements, especially uranium,” he adds with a smile.

    Bethe wanted to find the essence of why a dying star's core implodes. His key contribution, says Woosley, was to consider the star's entropy. As a star runs out of fuel and fuses heavier elements up to iron, Bethe found, the outer layers grow disordered while entropy declines at the blazing core. “Hans liked to say [the core] had the entropy of an ice cube, even though it was 10 million times hotter than hell,” Woosley recalls. Bethe calculated that when the core collapses, it has too little entropy for iron nuclei to break up. Instead, they compress into the extraordinary densities of neutron stars.

    That collapse ignites an outward shock wave, which the great mass of the star quickly snuffs out. Bethe believed neutrinos emitted by the newborn neutron star would relaunch the shock wave and drive the supernova blast, a scenario he published in his 80s with astrophysicist James Wilson of Lawrence Livermore National Laboratory in California. The verdict is still out; the best computer models have yet to blow up a simulated star in a convincing way.

    Solar neutrinos also captivated Bethe. With the late John Bahcall of the Institute for Advanced Study in Princeton, New Jersey, Bethe helped explain why underground detectors on Earth observed only a fraction of the neutrinos predicted to stream from the sun's core. Confirmation came from Canada's Sudbury Neutrino Observatory in 2001: The particles have minuscule masses and oscillate among different “flavors.” That behavior, as Bethe and Bahcall foresaw a decade earlier, arises from unknown physics beyond today's standard theory.

    Ablaze with energy.

    Neutrinos from our sun drew Bethe's focus late in his career.


    Neutrinos are so elusive that physicists still have no direct evidence of Bethe's carbon-nitrogen-oxygen cycle. That fusion should happen in our sun, albeit more sedately than in massive stars. “He would want us to verify that,” says physicist Wick Haxton of the University of Washington, Seattle. Doing so, however, will require sensitive new experiments—such as a proposal to place a 130-ton vat of liquid neon at Sudbury to spot low-energy neutrinos.

    Bethe also did not live to see a test of a claim that he, Gerald Brown, and Chang-Hwan Lee of Pusan National University in Busan, Korea, made—after Bethe turned 90—that binary systems containing two black holes should be 20 times as abundant as systems with one black hole and one neutron star. Their prevalence would be good news for the Laser Interferometer Gravitational-Wave Observatory (LIGO), which seeks the space-rippling disturbances caused by the mergers of such binaries. Two black holes should make a more violent “splash” in the gravitational pond of space, says theorist Kip Thorne of the California Institute of Technology (Caltech) in Pasadena, who motivated Bethe to probe the issue.

    An endangered generation

    The Laser Interferometer Space Antenna, long under development with the European Space Agency as a sensitive partner to LIGO, is one of three major space science missions planned by the astrophysics community in the next decade to peer further into Bethe's realm. The other projects are the four telescopes of Constellation-X, a high-resolution successor to the Chandra X-ray Observatory; and NASA's share of the Joint Dark Energy Mission, an effort with the U.S. Department of Energy to chart the weird speeding-up of the universe's growth and determine its cause. But funding prospects are dim (Science, 17 March, p. 1540). A tight NASA budget, combined with massive cost overruns and a huge backlog of proposed projects, has left them competing for what could be only one new NASA start for a major astrophysics mission in the next 3 years.

    The pain spreads to NASA's low-cost Explorers, which many view as the field's soul. Often led by universities, these missions draw students and yield outsized scientific results, says astrophysicist Roger Blandford, director of the Kavli Institute for Particle Astrophysics and Cosmology at Stanford University in Palo Alto, California. “You optimize the use of finite resources most efficiently by putting them into Explorer programs,” Blandford says. “Instead, NASA has been starving them to death,” including cancellation in February of the on-budget NuSTAR mission to image high-energy x-rays.

    Where next?

    In the post-Bethe era, astrophysicists face tough choices—and a hard act to follow.


    Some researchers at the meeting pinned these sacrifices on NASA's decision, after much political intervention, to fund a repair mission for the Hubble Space Telescope and to push ahead with its planned successor, the costly James Webb Space Telescope (JWST). “We could just see [Hubble] would be a $2 billion drag on the program,” says Turner, who recently completed a 3-year stint as head of mathematical and physical sciences at the National Science Foundation. Given all of NASA's other priorities, Turner says, moving forward with the repair without reconsidering its value within the entire suite of missions “was stupidity on stilts.”

    But other scientists believe that prolonging Hubble's life didn't automatically take money away from other programs because space science isn't a zero-sum game. Even with no servicing mission, “it's not clear that money would be made available for Explorers, or Constellation-X, or anything,” says astronomer Robert Kirshner of the Harvard-Smithsonian Center for Astrophysics in Cambridge, Massachusetts. He also notes that Bahcall led a National Academies' committee that in 2003 came out strongly in favor of at least one more NASA repair flight to the telescope, after extensive community input.

    More vexing for the long-term health of astrophysics is the ballooning cost of JWST, now pegged at $4.5 billion. “I worry that we've gotten ourselves into the SSC [Superconducting Super Collider] mentality, that we need $5 billion to do what's next, and everything else can go to hell,” says astrophysicist David Helfand of Columbia University. “We may suffer the same fate our particle-physics colleagues did 15 years ago,” he adds, referring to Congress's decision in 1993 to cancel the partially built accelerator in Texas. Astrophysicist Shri Kulkarni of Caltech paints the situation bluntly: “Is a single mission worth the rest of astronomy?”

    No one at the meeting had a good answer, and there was no consensus on how the community might gain the necessary political support for its priorities. Indeed, the room seemed infused with a wistfulness that Bethe couldn't be there to rally his colleagues in their time of need. “The scope of problems he could solve pretty much had no limit,” Brown wrote last year in Physics Today, recalling his struggle to keep up with a friend 20 years his senior. “In that sense, I think [Bethe] was the most powerful scientist of the 20th century.”

    • * Bethe Centennial Symposium on Astrophysics, Cornell University, 2–3 June.

Log in to view full text

Via your Institution

Log in through your institution

Log in through your institution