News this Week

Science  24 Oct 2008:
Vol. 322, Issue 5901, pp. 512

    Deep-Sea Scientific Drilling Hit By a Cost Double Whammy

    1. Richard A. Kerr

    As the oil industry gears up for the ongoing offshore-oil boom, scientists who study the sea floor say competition for scarce drilling resources is leaving them high and dry. “Funding goes down, oil goes up,” laments paleoceanographer Henk Brinkhuis of Utrecht University in the Netherlands. Facing soaring costs and lengthening delays, the United States component of the Integrated Ocean Drilling Program (IODP)—the current phase of the cooperative international investigation beneath the sea floor—has been literally stuck in dry dock, leading to an unprecedented 3-year hiatus in U.S. drilling. Japanese and European components of IODP are not faring much better. “I am very concerned about the long-term future of IODP,” says marine geologist Craig Fulthorpe of the University of Texas, Austin.

    Perhaps the worst blow came when the United States set out several years ago to refurbish and modernize its drilling platform, the JOIDES Resolution, or more familiarly, the JR. The $130 million renovation job had a fixed cost in a Singapore shipyard, but as the rising cost of oil spurred a surge of offshore drilling, the yard shunted the scientific ship to the side to focus on building and refurbishing drilling platforms for well-heeled oil companies.

    Under the resulting schedule pressure, the JR—originally programmed to resume drilling in October 2007—will be leaving the yard in early March 2009. This delay pushed two 8-week drilling cruises led by Fulthorpe and by Brinkhuis back a full year on less than 2 months' notice. “It is a disruption,” says Fulthorpe. Meanwhile, the competition with the oil industry hit the Europeans even harder. They had signed a short-term contract for onetime use of a special-purpose drill ship, but the owner of the vessel broke the contract to lease it to a higher paying oil company, Brinkhuis says. The European component of IODP has not drilled in 2 years.

    Tarrying too long.

    Competition from the oil industry for shipyard resources has delayed the return of the drill ship JOIDES Resolution.


    With work on the JR nearing completion, researchers now fear that budget cuts may curtail scientific drilling for years to come. U.S. operations are being funded well below expectations of a few years ago, says James Allan of the U.S. National Science Foundation (NSF), which funds the U.S. component of IODP. NSF funding amounts to almost a 20% cut in inflation-adjusted dollars, he says. Scientists also face three- to fourfold increases in the cost of drilling consumables such as steel liners for drill holes and a recently estimated $1-million-per-month rise in the cost of fueling the JR.

    As a result of the soaring costs, NSF now plans for the JR to devote only 70% of its time to IODP drilling. The Japanese behemoth ship Chikyu is likewise drilling for IODP only 60% to 70% of the time. Yet, there's plenty of science to be done. “There are now 30 drilling proposals [in the pipeline] that have been highly ranked,” says Brinkhuis. With the reschedulings plus the cutbacks in operating time, much of that science will be delayed and some never tackled at all, scientists worry.

    The JR's non-IODP time, everyone hopes, will be leased to a consortium of oil companies to drill holes of interest to both industry and scientists. But falling back on industry “is very discouraging for scientists,” says longtime ocean-drilling participant Theodore Moore Jr. of the University of Michigan, Ann Arbor. Industry and academia attempted a marriage of convenience 25 years ago (Science, 8 February 1980, p. 627) to no avail. “It's always been a difficult task linking industry and scientists' interests,” says Moore. Still, unless ship-fuel costs continue to ease, there is no other relief on the horizon.


    Media Policies Don't Always Square With Reality

    1. Eli Kintisch

    Most U.S. government agencies don't allow their scientists to talk freely with the media, according to a survey by an advocacy organization that has been highly critical of the Bush Administration's track record on scientific integrity. A new report ( from the Union of Concerned Scientists (UCS) gives some agencies relatively high marks for adopting policies that allow considerable openness but notes that those policies are not always followed. The culture in the majority of the 15 agencies UCS examined “has become [such that] talking with the press has become fraught with risks,” says UCS's Francesca Grifo.

    The Bush Administration has been involved in several high-profile incidents regarding the accessibility of government researchers, including the ability of climate scientists at NASA and the National Oceanic and Atmospheric Administration (NOAA) to speak openly about their research. So UCS decided to examine the written media policies at federal agencies and ask how well they are working in practice.

    Based on material from printed documents and agency Web sites, UCS gave grades of “excellent” or “good” to six of 15 agencies. (To keep the effort manageable, it omitted the Energy, Agriculture, and Defense departments.) The group also sent questionnaires to 6000 government scientists asking how those policies were implemented at their respective agencies. Based on a 12% response rate, UCS concluded that a minority of agencies were doing a good job (see pie chart).

    Pressing issue.

    Survey finds most science agencies need to improve how they handle media requests.


    The two lists don't necessarily match up. For example, UCS gave the Centers for Disease Control and Prevention an “A” for its policies and an “unsatisfactory” for its implementation of them, whereas the U.S. National Science Foundation earned an “outstanding” for allowing its science administrators free rein and an “incomplete” for not spelling out its policies. A 2007 law requires the White House to make sure all agencies have done so.

    UCS found that calls for openness from the boss don't always translate into more transparent operations. The director of the National Institutes of Health, Elias Zerhouni, emphasized “open scientific exchange” in a 2007 agencywide memo, but the UCS survey found NIH practices “not satisfactory” because scientists still need permission before speaking to reporters. (“It's primarily an FYI rather than an approval process,” says an NIH spokesperson.) In contrast, following incidents at their agencies, the directors of NOAA and NASA told their managers to give agency scientists more leeway. As a result, says Timothy Donaghy of UCS, the situation is “a lot better now.”


    Cardiologists Come Under the Glare of a Senate Inquiry

    1. Jocelyn Kaiser

    Research universities are nervously viewing an expanding Senate inquiry into alleged financial conflicts of interest among faculty members. Last week, Columbia University came under the spotlight. Senator Chuck Grassley (R-IA) publicly challenged the university to explain the industry ties of a group of Columbia cardiologists who work with a nonprofit that receives funding from medical device makers. This money may be biasing some faculty members' views on stents and other heart devices, Grassley suggests.

    Grassley zeroed in on the Cardiovascular Research Foundation (CRF), which conducts clinical trials on devices and drugs, according to its Web site. It also holds an annual educational conference. Three Columbia cardiologists sit on CRF's board; others are listed as “leadership” or “affiliated” physicians. In a 16 October letter to Columbia president Lee Bollinger, Grassley and Senator Herb Kohl (D-WI) request details on outside income for about 20 of these faculty members. In a similar letter to CRF they write: “We are … concerned that funding from the medical device industry may influence the practices of non-profit organizations that purport to be independent in their viewpoints and actions.”

    Widening net.

    Senator Grassley probes a nonprofit linked to Columbia University.


    Columbia and CRF say they will respond to the questions. Although none of the Columbia faculty members appears to have grants from the U.S. National Institutes of Health, and therefore may not come under NIH's rules, the university has its own conflict-of-interest policies and “expect[s] that they are followed by all … faculty,” Columbia says. Although it may not be unusual for industry-funded charities to have ties to academic medical centers, some observers see a potential problem. “I suspect that individuals set these [charities] up to bypass university oversight procedures,” suggests health policy expert Eric Campbell of Harvard Medical School in Boston.

    But Susan Ehringhaus of the Association of American Medical Colleges in Washington, D.C., cautions against generalizing. The important first step, she says, is that industry funds be fully disclosed. CRF's Web site states that it has corporate funding, and two of its Columbia directors acknowledged in an article in The Lancet last year that the foundation has ties to four companies.

    The Columbia inquiry came as a related probe of financial conflicts among NIH-funded researchers was heating up. Last week, news emerged that NIH recently responded to concerns about an Emory University psychiatrist by taking a rare step: It suspended a grant to the university after Grassley alleged that principal investigator Charles Nemeroff had failed to report at least $1.2 million in outside consulting income (ScienceNOW, 14 October: The $9.3 million, 5-year study comparing depression treatments was transferred to another faculty member in July, but NIH halted funding in mid-August, Emory says. The frozen grant has put universities on high alert to get their conflict-of-interest policies in order, says one biomedical research lobbyist.


    Global Warming Throws Some Curves in the Atlantic Ocean

    1. Richard A. Kerr

    It was an ominous if subtle shift in the far North Atlantic. For 30 years, waters off southern Greenland and Iceland had been growing less and less salty, oceanographers reported in late 2003. It looked as if global warming could be freshening high-latitude Atlantic waters (Science, 2 January 2004, p. 35). If the trend continued, they worried, it could throw a monkey wrench into the “conveyor belt” of currents that warms the far North Atlantic, as is wildly overdone in the movie The Day After Tomorrow. New analyses have now shown that global warming is indeed messing with the Atlantic's salinity, although not as dramatically as Hollywood envisioned.

    The first explicit link between global warming and ocean salinity changes comes in a study in press in Geophysical Research Letters. Modeler Peter Stott of the Met Office Hadley Centre in Exeter, U. K., and his colleagues simulated changing ocean salinity in the center's HadCM3 climate model with and without increasing greenhouse gases. Under past global warming conditions, the model produced salinity changes around the world much like those seen. But only in the subtropics and mid-latitudes of the North Atlantic—between 20°N and 50°N—did salinity change significantly more than the natural jigglings of the climate system would have changed it.

    The increase in salinity in North Atlantic mid-latitudes thus carries the “fingerprint” of human influence left by the effects of human-generated greenhouse gases, the group concludes. Greenhouse warming there apparently removed more water by evaporation while precipitation decreased, concentrating seawater's salts. “It looks convincing to me,” says climate modeler Gabriele Hegerl of the University of Edinburgh, U. K. The signal is only now emerging, she adds, but “it looks very consistent with what is expected.” She and others would like to see additional models replicate the fingerprinting, just to be sure.

    Although global warming seems able to alter even the saltiness of the sea, it hasn't noticeably freshened the high latitudes of the North Atlantic, as some researchers thought it might be doing back in 2003. When run without rising greenhouse gases, the Hadley model produces so many salinity swings up and down through natural processes built into the climate system that any greenhouse fingerprint would have been smudged beyond recognition, the group found.

    But global warming isn't finished with the far North Atlantic, at least according to the Hadley model. Run out to the end of the century under a strengthening greenhouse, it simulates a precipitous dip in northern salinity from a recent upturn and then a rapid recovery by 2100 (see figure). That roller-coaster ride “rings true,” says physical oceanographer Ruth Curry of Woods Hole Oceanographic Institution in Massachusetts. Since publishing the observed freshening trend in 2003, she has come to understand that natural swings in atmospheric circulation over the North Atlantic—the so-called North Atlantic Oscillation (NAO)—have alternately driven fresher water from the Arctic and then saltier water from low latitudes into the far North Atlantic. Those shifts, rather than global warming, have dominated high-latitude salinity, with an NAO-driven switch from fresher to saltier coming in the mid-1990s.

    No biggie, yet.

    With (red) or without (green) greenhouse conditions, a model produced much the same variations in ocean salinity as observed (blue), but the variability could increase.


    The next decades-long swing in northern salinity will be large because global warming is increasing the stores of fresher water in the Arctic and of saltier water in the far south, Curry says. “I would expect some weakening of [conveyor belt] currents” as the next freshening sets in, she says, “but that's not the biggest worry.” The biggest worry, she says, is losing all Arctic sea ice to global warming.


    Clinical Trials Guidelines at Odds With U.S. Policy

    1. Dennis Normile*
    1. With reporting by Eliot Marshall.

    Aiming for consensus on some long-debated issues in clinical research, the World Medical Association (WMA) adopted a revised ethics manifesto at its meeting last week in Seoul, South Korea. WMA's guidelines, known as the Declaration of Helsinki, have long been used by regulatory agencies around the world as the basis of rules governing the conduct of clinical trials, although the U.S. Food and Drug Administration (FDA) is in the process of moving to a different—some say less demanding—set of ethical standards.

    The revisions approved last week include sharper limits on the use of placebos and stronger language requesting that trial sponsors care for all participants after a trial is finished. In a new provision that's likely to prove controversial, WMA asks sponsors to register clinical trials in publicly available databases before recruiting the first subject. Even WMA's leaders concede that these changes in the declaration may not be the last word.

    Since its adoption in 1964, the Declaration of Helsinki has been amended five times, most recently in 2000. Debate continued as footnotes were added. “It was obvious that the notes of clarification actually did not clarify something that was really confusing,” says Eva Bågenholm, who chairs the WMA committee on ethics and is president of the Swedish Medical Association in Stockholm.

    The new language on the use of placebos in clinical trials is likely to attract the most attention. For decades, the gold standard in new-drug development has been a randomly assigned trial that compares the effects of a new intervention with those of a placebo. But many worry that such trials in effect deny care to those who draw the placebo, often at great cost to their health.

    The Helsinki Declaration's original 46-word paragraph on the use of placebos said that new interventions should be tested against the best, proven existing interventions; placebos could be used when no proven interventions existed. A 136-word note of clarification, adopted in 2002, said “a placebo-controlled trial may be ethically acceptable, even if proven therapy is available” when compelling scientific and methodological reasons made its use necessary to determine the efficacy or safety of a new intervention. The new amendment leaves little room for maneuver: It states that “a new intervention must be tested against … the best current proven intervention.” A placebo is acceptable “where no current proven intervention exists” or where its use is necessary to determine an intervention's efficacy or safety, and patients who receive placebos will not be subject to any risk of harm. The relevant paragraph concludes, “Extreme care must be taken to avoid abuse of [the placebo] option.” Even so, Bågenholm recognizes that this language did not resolve all the underlying controversies. “There are still some people who are not happy with the paragraph [on using placebos],” she says.

    Middle ground.

    Swedish physician Eva Bågenholm helped draft a compromise on the use of placebos.


    On post-trial care, the ideal would be to assure participants of some level of continuing medical support, says Jeff Blackmer, executive director for ethics at the Canadian Medical Association (CMA) in Ontario. The new paragraph reads: “At the conclusion of the study, patients entered into the study are entitled to be informed about the outcome of the study and to share any benefits that result from it, for example, access to interventions identified as beneficial in the study or to other appropriate care or benefits.” But Blackmer says the financial burden of providing such care could hinder the development of drugs for neglected diseases affecting the world's poor. “The CMA is supportive of the new wording of the paragraph,” although it's “probably not perfect,” he says.

    The new proposal calling for registration of clinical trials before recruitment of the first patient is not likely to be followed by industry. In comments submitted to WMA before the Seoul meeting, the Biotechnology Industry Organization (BIO) in Washington, D.C., said it supports the goals of transparency and access to clinical trial information. But it worries that registration of all trials might jeopardize intellectual property rights and frustrate R&D efforts while providing little guidance to prescribers and patients. BIO suggested that the declaration exclude phase I trials, typically the first inhuman tests, from registration.

    The Pharmaceutical Research and Manufacturers of America, also in Washington, D.C., suggested dropping the requirement to register prior to the recruitment of the first patient because it “creates a major burden for trial sponsors and could significantly delay trials.” Bågenholm says that although aware of industry concerns, “we think any trial that involves people should be registered to protect them” and to avoid having them go through repeated testing of the same intervention.

    Coincidentally, the amendments were adopted just a week before an FDA decision takes effect that will let applicants for new drug approvals bypass the Declaration of Helsinki when conducting certain trials overseas. Instead, FDA will ask applicants to comply with the International Conference on Harmonization's Good Clinical Practice (GCP), which some view as having far less rigorous ethical standards. “The decision would seem to encourage pharmaceutical companies to cut ethical corners when working abroad,” says Stuart Rennie, a bioethicist at the University of North Carolina, Chapel Hill. He says GCP is more open to the use of placebos and does not mention conflicts of interest, the need to publish results, or post-trial access to care.

    Any suggestion that FDA is relaxing its policy on human subjects' protection is “absolutely not true,” says FDA Associate Commissioner Rachel Behrman. She says FDA regulations have dropped references to the Declaration of Helsinki because some of WMA's policies—such as the bias against placebos—are “not consistent with U.S. law,” not subject to a U.S. veto, and could create a “confusing” situation.

    Edward Hill, chair of WMA and former president of the American Medical Association, notes that WMA has established a new working group to continue to study the placebo issue.


    'Spore' Documentary Spawns Protest By Scientists Who Starred in It

    1. John Bohannon

    CAMBRIDGE, MASSACHUSETTS—The National Geographic Channel is often praised for its meticulous science documentaries, but a show that aired last month focusing on the blockbuster video game Spore is coming in for harsh criticism. Surprisingly, the toughest critics are some of the scientists who appear in the film itself. They say that they were not informed before taking part that it would focus on a commercial product. “I literally never heard about Spore until I saw myself on television in this infomercial about the game,” says Cliff Tabin, a geneticist at Harvard University. “It's an outrage.”

    The documentary, titled How to Build a Better Being, which aired on 9 September, puts Spore and its creator, Will Wright, front and center. Over the course of the 1-hour show, Wright visits several U.S.-based academic scientists to discuss their research. Between these scientific interludes, the documentary returns to Wright and Spore. “Journey into the billion-year history of the human body, led by computer game visionary Will Wright as he explores the breakthrough science that's revealing the secret genetic machinery that shapes all life in the game Spore,” reads a description of the film on the National Geographic Channel's Web site.

    Tabin, along with Neil Shubin, a paleontologist at the University of Chicago in Illinois, and Michael Levine, a geneticist at the University of California, Berkeley, sent Science identical e-mails from the film's producers inviting them to take part. The e-mail describes the documentary as an investigation of “recent discoveries in evolutionary science” with no mention of Spore or Wright. “I thought I was being interviewed for a documentary about evolutionary biology,” says Shubin, who appears to be playing the game in the film. “They didn't mention Spore until we were in the middle of [the interview]. … I sat there with Will Wright as he fiddled with it,” he says. “I don't endorse video games, particularly one that claims to be about evolution.”

    Ellen Stanley, National Geographic's communications vice president, says there was no intent to mislead the participants. “Our producers were transparent with all of the scientists,” she says. The production of such a documentary takes “several months” she adds, and “the idea for the film evolves during that process.”

    Spore is described in the film as “one of the most ambitious games ever, simulating the process of evolution,” and a DVD of the film is included in the $80 “Galactic Edition” of the game. “There's no question that the impression one gets from watching [the film] is that Spore is scientifically based and that scientists endorse this as not only a valid representation of how life on earth arose but moreover a really cool way that kids can learn about it,” says Tabin. But “the science is told in the most superficial way and not really explained or clarified,” he says. “And then it becomes more about this computer game designer than it is about the science.” (A panel of scientists asked to review the game's scientific content for an online Science feature,, gave its treatment of evolutionary biology low marks.)

    Designer creature.

    Biologists complain that they appear to be endorsing the video game Spore in a National Geographic film.


    Stanley declined to comment about the relationship between National Geographic and Spore's manufacturer, Electronic Arts. “We had a great time partnering with the folks over at National Geographic,” wrote a spokesperson for Electronic Arts in an e-mail to Science. “However, we don't typically discuss business terms of our partnerships.”


    In Brief: Where They Stand on Science Policy

    At the risk of oversimplifying these complex topics, the news staff of Science has boiled down what Senators John McCain and Barack Obama have said during the long campaign about some three dozen important issues.

    At the risk of oversimplifying these complex topics, the news staff of Science has boiled down what Senators John McCain and Barack Obama have said during the long campaign about some three dozen important issues

    Download the PDF here.


    A Full Serving of Science Awaits the Next President

    Many scientific issues are never discussed during the campaign. But ignoring them doesn't make them disappear. Here are 10 meaty topics that we think the 44th president will have to chew on.

    Many scientific issues are never discussed during the campaign. But ignoring them doesn't make them disappear. Here are 10 meaty topics that we think the 44th president will have to chew on

    The Act of Regulating CO2


    Both candidates say curbing U.S. greenhouse gas emissions will be a top priority in their respective Administrations. But getting Congress to pass a strong mandatory cap-and-trade system may take years. So the next president will have to decide whether to regulate carbon dioxide emissions by using the authority granted the executive branch under the Clean Air Act. Last year, the U.S. Supreme Court ruled that greenhouse gases are a pollutant that the government can regulate. McCain says he doesn't think the act is the appropriate vehicle, whereas Obama says he might use it if lawmakers dawdle on legislating greenhouse gas limits. Climate scientists say there's no time to waste.

    Cold Cash for the Poles


    The shrinking Arctic ice cap is expected to trigger an economic free-for-all among polar-going nations seeking to take advantage of shorter shipping routes and untapped natural resources. Ironically, less sea ice will increase demand for icebreakers capable of ensuring safe passage through the once-inaccessible region.

    Although several European nations have beefed up their fleets in response to such opportunities, the Bush Administration has gone in the opposite direction: Three years ago, it shifted budgetary responsibility for three icebreakers from the U.S. Coast Guard to the National Science Foundation, arguing that science is the biggest user at both poles. The House of Representatives has voted in favor of building two new icebreakers, in line with recommendations in a 2006 U.S. National Academies report. An Arctic policy review being completed by the current Administration is expected to tee up the issue for the next president, who must decide whether to seek funding for the billion-dollar ships.

    Pick a Planet


    The next president may have a lot to worry about at home, but he'll also have to think about the outer solar system. NASA plans to decide in January whether to launch a multibillion-dollar spacecraft to Jupiter or Saturn, kicking off work on the agency's most ambitious space science effort in its 50-year history. That means the agency will need increasing chunks of annual funding, starting in the 2010 fiscal year that begins next October, to begin design of a spacecraft that will visit one of the two planetary systems. Launch of the probe, which may include landers for jovian or saturnian moons, would likely come near the end of the next decade. McCain has been silent on NASA's space science effort, but Obama has pledged to support a new generation of probes. The victor may also hear from advocates for a sample-return mission to the Red Planet instead.

    Small Comfort

    Long touted as the next “big thing,” nanotechnology is already moving from research to market. Some $50 billion worth of products already contain nanomaterials, according to a 2006 estimate. But safety concerns continue to dog the emerging field. Nanomaterials are easily absorbed by a variety of cells and tissues, with largely unknown effects. A bill to increase funding for nano safety studies and better coordinate research among the 25 agencies in the government's National Nanotechnology Initiative failed to make it through the current Congress. The Bush Administration appeared willing to go along with the additional funding but didn't see the need for additional coordination. The next president must decide if the country needs to revise its nano safety strategy to strengthen protections for the public.

    Being a Team Player


    Can the United States be a reliable partner in international scientific collaborations? This year's elimination by Congress of the U.S. contribution to the $15 billion ITER project, an experimental fusion reactor to be built in France, highlights the incompatibility of paying for decade-long construction projects with annual appropriations bills. U.S. proponents of the proposed International Linear Collider shake their heads when asked if their government can be counted upon, especially if the electron-smasher isn't built on U.S. soil. But multiyear spending approval is probably a pipe dream. So although both candidates may pledge allegiance to the principle of global cooperation in science, the winner will need to maintain good ties with Congress to deliver on any agreement to share the cost of expensive new scientific facilities.

    Combating Bioterrorism


    The new Administration will likely need to decide how institutions and researchers should conduct life sciences research in ways that reduce the chances the results could be expropriated by terrorists. The National Science Advisory Board for Biosecurity (NSABB), set up in 2005, has drafted rules for the oversight of such research that include getting scientists to indicate if their projects could be misused and having institutional committees review projects that raise a red flag. NSABB submitted the oversight framework last year to the Department of Health and Human Services. But the Bush Administration is not expected to finish the job before it leaves office. Obama and McCain have not raised the issue during the campaign.

    Taking (Nuclear) Stock

    At 65, the U.S. nuclear weapons complex is showing its age. The Pentagon keeps reducing the size of the stockpile as Congress ponders whether to consolidate the $6.3 billion-a-year enterprise. More than 2000 staff positions have been erased since 2006 at the flagship Los Alamos and Lawrence Livermore labs, cuts that some blame on budget pressures caused by the high fees charged by new corporate management. The next president is scheduled to lay out his goals in a December 2009 stockpile review, which both labs hope will include developing a new weapon. Obama and McCain have neither explicitly supported the deployment of new warheads nor said they would end research on developing new weapons.

    Providing Some Assistants

    John Marburger's job is to advise President George W. Bush. But he doesn't hold the title of assistant to the president for science and technology, and his office is half a block from the White House. Those two aspects of the job diminish his effectiveness, according to three recent reports by science policy mavens, who say that science ought to have a higher profile in the next Administration. Both candidates have talked about restoring “integrity” to the process of making science-based decisions in their respective Administrations and pledged to fully staff the Office of Science and Technology Policy that Marburger runs. This month, Obama also promised to upgrade the title of his science adviser. Will that be enough to give science a real seat at the table of power? Stay tuned.

    More Intelligent Medicine

    No buyer of drugs and medical devices spends more—or has a greater ability to influence the quality of medicine—than the U.S. government. But programs like Medicare avoid any direct consideration of cost when they buy a new therapy. That may change. Facing a widening deficit in the federal budget, the next Administration will have an incentive to vet big-ticket proposals—such as CT screening for lung cancer or exotic drugs that offer minimal benefits—before accepting them. Advocates of evidence-based medicine in Congress have proposed a new research center that would explicitly compare diagnostic technologies and treatments based on public value. Shunted aside in 2007-08, the idea is likely to return as the need grows for rational decision-making.

    Fishing for Answers

    Many U.S. fisheries remain in crisis, especially some commercially important species on the East Coast that remain chronically depleted. The next president will have to decide whether to mobilize the government to stop overfishing. Congress told the nation's eight Fishery Management Councils 2 years ago to achieve that goal by 2010 when it reauthorized the major U.S. fisheries program (Science, 22 December 2006, p. 1857). Some councils have resisted, but the National Oceanic and Atmospheric Administration's National Marine Fisheries Service has the authority to reject catch limits that aren't strict enough. Although both candidates say they support sustainable fisheries, neither has spelled out how he would make it happen.


    Eyeing Oil, Synthetic Biologists Mine Microbes for Black Gold

    1. Robert F. Service

    Biotechnology researchers want to reengineer microorganisms to turn agricultural products into gasoline, diesel, and jet fuel.

    Biotechnology researchers want to reengineer microorganisms to turn agricultural products into gasoline, diesel, and jet fuel

    EMERYVILLE, CALIFORNIA—What do you do after creating a cheap antimalarial drug that could save millions of lives in the developing world? If you're Jay Keasling, you tackle two equally pressing problems: climate change and the need for abundant renewable fuels.

    Keasling, a synthetic biologist at the University of California, Berkeley, made a splash a few years ago when he and his colleagues reengineered two microbes—Escherichia coli and baker's yeast—to churn out a costly plant-derived antimalarial compound called artemisinin. Now, Keasling and dozens of colleagues working at the Joint BioEnergy Institute (JBEI) that he directs are trying to create classes of compounds, such as alkanes, that are key components of gasoline and other transportation fuels. “Artemisinin is a hydrocarbon,” Keasling says. “We're just trying to engineer organisms to produce different hydrocarbons.”

    Keasling hopes to leapfrog over a bitter debate among agricultural economists about the value of ethanol, the first-generation biofuel. Keasling and a handful of others are starting from scratch, using synthetic biology to lend E. coli, yeast, and other easily grown microorganisms the ability to create mixtures of compounds that can be used to make various things, including gasoline, jet fuel, plastics, and cosmetics. “This is just at the beginning,” says Keasling, sitting in his fourth-floor office with a view of the Berkeley campus and the Oakland hills. The combination of rapidly improving bioengineering technology and the massive pull for cheap, low-net carbon fuels has generated enormous excitement, he asserts. “This is just a golden period for this area.”

    The question is whether it will be black gold. A handful of start-up companies have leapt into the field, some even teaming up with major energy companies such as Chevron and BP. Some of these companies have already begun producing fuels, but none say they can beat the price of conventional petroleum, despite its recent spike to more than $140 a barrel. But with technology improving rapidly, “very likely it can be done,” says Vinod Khosla, a venture capitalist with Khosla Ventures in Menlo Park, California, who has backed several next-generation biofuel start-ups.

    Black gold.

    Algae (below) produce oils that are converted into biodiesel.


    For now, most of the new biofuel producers have set their sights on displacing ethanol rather than gasoline and diesel. According to the Renewable Fuels Association, last year the world produced more than 50 billion liters of ethanol fuel. Most of it is made by fermenting food crops—corn kernels in the United States and sugar cane in Brazil.

    Critics argue that this method is driving up food costs. The production of corn-based ethanol, they say, requires nearly as much energy from fossil fuels to drive the tractors, produce fertilizer, and run the ethanol plants as what comes out in the alcohol at the end. The end result, they argue, is at best a marginal reduction of carbon dioxide (CO2). In addition, ethanol can't be shipped through existing oil pipelines because it mixes easily with water, which accumulates in the pipelines.

    With so many strikes against ethanol, most synthetic biology groups are working to engineer microbes to produce fuels essentially identical to existing fossil fuels. They want bugs that can grow on the sugars from agricultural waste and other “cellulosic” materials, thereby reducing the need to use scarce agricultural land to grow fuels.

    The early results are heartening. Keasling and his colleagues, for example, are having early success at reengineering E. coli to produce gasoline-type molecules. The work builds on Keasling's earlier triumph with artemisinin. In that case, Keasling's team focused its efforts on metabolic pathways in E. coli and yeast that normally produce small amounts of compounds called isoprenoids, precursors for building many pharmaceuticals such as artemisinin, among other chemicals.

    Keasling's team made about 50 genetic changes—adding genes for additional enzymes, promoters, and so on—to the organisms to get them to convert these intermediate compounds to artemisinin. Keasling founded Amyris Biotechnologies, which shares space in the JBEI facility, to commercialize the work. Initially, the bugs produced only tiny amounts of artemisinin. But by outfitting E. coli and yeast with several new genes and turning off the expression of others, Keasling and his colleagues at Berkeley and Amyris boosted a millionfold the production of the antimalarial.

    That's good enough to match the average price of artemisinin, about $1 per gram. But Keasling notes that they will have to do even better to make microbial fuel cost-effective, because the production of fuel molecules at $1 per gram translates into a price of about $125 a liter for gasoline. “It has to be cheaper than water,” Keasling says. To do that, the team needs to engineer the microbes to increase the flux of the starting material—sugar in this case—through the microbes' fuel-producing pathway.

    At a meeting last month in Hong Kong,* Keasling reported on a novel strategy to increase the chances that the product of one reaction inside this pathway is properly handed off to the next enzyme in the chain. The team engineered E. coli to express a protein scaffold for a trio of enzymes that work in their isoprenoid pathway and bind them in a way that more efficiently transforms starting compounds to the final result. “This increased the flux through the pathway 77-fold,” Keasling says. At Amyris, Senior Vice-President of Research Jack Newman says the company is also making significant headway on producing renewable diesel and jet fuel. Amyris has teamed up with Crystalev, one of Brazil's largest ethanol producers, to scale up the company's proprietary technology to make renewable fuels from sugar cane, beginning in 2010.

    Across San Francisco Bay in South San Francisco, researchers at LS9 are reengineering E. coli and other organisms to make what they refer to as renewable petroleum. Rather than co-opting the microbe's isoprenoid pathway, LS9 researchers are focusing on the pathway that converts sugars to fatty acids, which can then be converted to biodiesel.

    Gregory Pal, LS9's senior director for corporate development, notes that fatty-acid biosynthesis is the main route by which organisms convert excess energy into fats. Most organisms have evolved to do this quickly and with high efficiency, as anyone who has tried dieting knows all too well. “We've made on the order of dozens of [genetic] transformations” to maximize that efficiency, Pal says. The company, he adds, has successfully produced a variety of hydrocarbons and is now focused on scaling up the technology. LS9 already has a pilot-scale fermentation facility up and running at its headquarters and plans to open a small-scale production facility by mid-2010.

    Variety show

    . Researchers are trying a host of approaches to microbial hydrocarbon fuels.


    James Liao and colleagues at the University of California, Los Angeles, are trying a third approach. In the 3 January issue of Nature, Liao and his co-authors described how they engineered E. coli to produce isobutanol, a longer chain alcohol than ethanol. That increased chain length gives isobutanol a more energetic punch per liter and enables it to be separated from water more easily, Liao says. The molecule can also easily be converted to fuels that can be blended with gasoline as well as transformed into other commodity chemicals.

    Like other groups in the field, Liao has his own favored biosynthetic pathway. He and his colleagues have co-opted the metabolic pathway that bugs use to convert common starting materials, called alpha-keto acids, to amino acids. Liao focused on this pathway because it is already adapted to handle large fluxes of hydrocarbons. “Fiftyfive percent of the cell's composition is protein, so it needs a lot of amino acids,” Liao says of the E. coli microbe his team is working with. Liao has teamed up with Gevo, a bioenergy start-up in Pasadena, California, that he says is building a pilot production plant. Liao also notes that his group is making progress on getting photosynthetic bacteria to make isobutanol. The goal is for bacteria to manufacture fuel simply by absorbing sunlight and CO2.

    Getting photosynthetic organisms to produce fuel directly has long been the dream of researchers working with algae that can absorb sunlight and CO2 to produce plant oils that, in turn, can be converted to biodiesel. But the technology has been plagued by real-world challenges such as the need to harvest algae from large, shallow ponds and separate out the oils.

    Another biofuel start-up, Solazyme in South San Francisco, hopes to avoid those pitfalls. Solazyme researchers are working with natural and engineered algal strains to produce what they refer to as renewable biodiesel. Instead of growing their algae outside in the sunlight, Solazyme researchers grow them inside dark stainless steel fermenters, in which the organisms convert sugars to oils. Turning off the algae's photosynthetic apparatus enables the organisms to produce oils more efficiently and makes it less costly to recover, says Harrison Dillon, Solazyme's president and chief technology officer.

    The company can already produce biodiesel by the barrel and has had separate versions certified as jet fuel and biodiesel. Solazyme has managed to move quickly, Dillon says, because many of the algal strains start out as efficient oil producers. “They are naturally a long way towards where you want them to be,” he says.

    Are any of the next-generation biofuels likely to succeed? Khosla and others say the technology has several distinct advantages. First, synthetic biology allows researchers to test hundreds of potential improvements in a short time. “That means we can not only iterate quickly but not stop iterating,” Dillon says. And Khosla adds that unlike renewable-energy technologies such as wind and hydropower, the economics of the technology improve as it is scaled up, allowing companies to take advantage of large-scale production efficiencies.

    Finally, it's doubtful any biofuel start-up will be beat out by other upstarts. “The demand for fuels is so huge, there will be multiple winners out there,” Dillon says. “If you make it at the right price, you can sell as much as you can produce.”

    Still, for the near term, microbial biofuels will remain dependent on food-based agriculture to generate the sugars needed to feed the bugs. And even if cellulosic wastes can be economically converted to sugars, some wastes will likely need to be left on agricultural and forest land to return needed nutrients to the soil. Despite those drawbacks, Khosla says, next-generation biofuels won't remain a research project for long. “They're a lot closer to market than the time it takes to build a new oil refinery,” he says.

    • *Synthetic Biology 4.0, Hong Kong University of Science and Technology, 10-12 October.


    Last-Ditch Effort to Save Center at Vanguard of Stem Cell Research

    1. Elizabeth Finkel*
    1. Elizabeth Finkel is a writer in Melbourne, Australia.

    After ousting its CEO and board, the Australian Stem Cell Centre hopes to regroup around a plan that rebalances research and commercial goals.

    After ousting its CEO and board, the Australian Stem Cell Centre hopes to regroup around a plan that rebalances research and commercial goals

    Niche players.

    ASCC's David Haylock, postdoc Jochen Grassinger, and Suzie Nilsson are developing an artificial niche to get stem cells to behave better in culture.


    MELBOURNE, AUSTRALIA—The moment of truth has arrived for a faltering attempt to kick-start Australia's stalled biotech industry. In July, the board of the Australian Stem Cell Centre here sacked CEO Stephen Livesey over disagreements about how quickly ASCC should seek to spin off products. A month later, the board itself stepped down. “From 1000 feet, it looks like a disaster,” says ASCC founder Alan Trounson, who left in 2003. After a traumatic several weeks, a concerted effort is under way to steer ASCC back on course: An interim board is drafting a new strategic plan that was expected to be presented to the 10 ASCC consortium members and the government after Science went to press.

    ASCC's future depends on whether the government's Department of Innovation, Industry, Science and Research, which has bankrolled the center's initial 9 years, will accept the new plan. “There's excellent research going on, but the business model just wasn't going to work,” in part, because of its emphasis on rapid commercialization, argues endocrinologist and former CEO of the Australian Research Council Vicki Sara, who chaired the ASCC board that resigned en masse.

    ASCC follows a hub-and-spoke model, in which a central administration based at a biotech park on the grounds of Monash University (MU) reviews and funds projects proposed by consortium members. “The center is all about building collaborations and big thematic programs that would not be possible otherwise,” says director of ASCC research services and hematologist David Haylock.

    Real McCoy.

    This bone marrow niche regulates development of blood-forming stem cells; red stain is for osteopontin, green is for tenascin C.


    According to its charter, ASCC must also commercialize its research. But from the get-go, the center's leadership has been arguing over how that should happen. The previous board asserted that ASCC should capitalize on its research through patents and licensing agreements. Livesey was keen on pushing a product through the pipeline and spinning off a company to attract outside investment. “I've always been a risk taker,” Livesey says. “But clearly that degree of risk-taking wasn't for everyone.”

    ASCC came into being in 2002, at the height of a fervor to raise the game of Australian scientists. Two years earlier, a major review attributed the paltry payoff from biotechnology to a lack of critical mass and a poor culture of commercialization (Science, 13 October 2000, p. 255). To remedy the situation for biomedical researchers, the federal government invited bids for a $24 million grant to create a biotechnology center of excellence. A consortium led by Trounson, then of MU, won the competition. Australia had a leading reputation in the field largely because Trounson's group had come in a close second to James Thomson's team at the University of Wisconsin, Madison, in the race to isolate human embryonic stem cells. Given constraints on federally funded U.S. researchers, Australia had a strong chance to stake claims in a potentially rich new biomedical field.

    ASCC's consortium—at the time, seven Australian universities and medical research institutes—appointed Trounson as CEO. He then recruited Livesey as chief scientific officer. An Australian who had founded the U.S. biotech company LifeCell, Livesey seemed a natural choice: He had nurtured a successful biotech venture whose lead product—AlloDerm, artificial tissue for burns and reconstructive surgery—is derived from human tissue.

    But soon, Trounson and Livesey weren't seeing eye to eye. A major schism opened over the center's direction, Trounson says. Livesey wanted ASCC to develop a product, and revenue stream, within 9 years. Trounson saw ASCC as fundamentally research-driven. “Stem cell science needs a really long period of research,” he says. “I couldn't see how you could commercialize in that time frame.”


    ASCC's board, then chaired by biomedical entrepreneur Bob Moses, sided with Livesey. Trounson left to found the Monash Immunology and Stem Cell Laboratories; in 2007, he became president of the California Institute for Regenerative Medicine in San Francisco. Hugh Niall, former CEO of Biota, one of Australia's few successful biotech companies and until then a founding director of ASCC, took over as CEO.

    ASCC placed its commercial bet on developing blood cell products and spinning off a start-up by 2011. First would be a novel “off the shelf” treatment for cancer patients: neutrophils derived from stem cells in cord blood or donated blood, based on research by an ASCC-funded lab led by Lars Nielsen at the University of Queensland. Other projects in the pipeline were drug candidates to replace hormones now used to stimulate blood cell regeneration in cancer patients, a stem cell bioreactor, and blood products from embryonic stem cells. Nevertheless, 90% of ASCC's R&D budget has been invested in basic research, on projects such as how to coax stem cells to form blood, lung, and kidney tissues.

    In 2006, an independent review by an outside company in Spit Junction, Australia, called Growing Your Knowledge gave the center high marks and helped ASCC secure an additional $41 million in government funds. But it also warned that management, board, and consortium members lacked a common vision for ASCC's future. Later that year, Niall stepped down as CEO to rejoin ASCC's board, and Livesey took the reins. By early 2007, says Livesey, “I ran into problems. … People weren't pulling in the same direction; there was significant dysfunction in the center.”

    Sara says the board was uncomfortable with Livesey's focus on commercialization, even though those efforts consumed just 10% of the R&D budget. The board instructed ASCC to modify its deed of agreement with the government, which had stipulated that the center's mission is to provide therapeutic and commercial benefits from stem cell products. The amended deed, says Livesey, stated that the center simply “should pursue excellence in stem cell research.”


    To bring matters to a head, Livesey wrote an aggressive 5-year business plan that would have expanded the budget devoted to commercial ventures. “I knew termination was one of the significant possibilities, but the success of the center was extremely important,” he says. The board ordered Livesey to rewrite the plan with a narrower commercial focus. He did. But the innovation department rejected the revised plan, because, Livesey contends, “it did not have a fully defined commercialization strategy.” Officials at the innovation department declined to comment.

    Last July, the board asked Livesey to resign. “It was the opinion of the board that we need to build national capacity, not focus on short-term products. We needed new leadership for that,” says Sara. But ASCC's consortium members had had enough of being relegated to the sidelines of ASCC's business affairs. They wanted to assume greater control of the situation, sources say. The board was purged, and an interim board was established with representatives from three consortium members—MU, the University of Queensland, and Melbourne's Howard Florey Institute—led by an independent chair, Graham Macdonald, former medical director of Merck Sharp & Dohme in Australia. With input from the consortium, Macdonald is now crafting a new plan for the remainder of the center's initial 9-year funding, which expires in June 2011, and beyond. “The board's job is to develop a model with buy-in from all the stakeholders and to present the government with plan B,” Macdonald says. That could steer ASCC in one of two directions, he says: either keep the hub-and-spoke form—which earlier this year was pared down to Melbourne and Queensland, with a small contribution from New South Wales—or transform the center into a funding organization. A final plan was expected to be hammered out at a workshop on 24 October.

    Most observers say that staking ASCC's success on a product was unrealistic and unnecessary. “We think there will be other ways of sustaining the center beyond 2011,” such as entering into partnerships with biotech companies, providing stem cell-cultivation services, and intellectual property consulting, says acting CEO David Collins.

    ASCC scientists are hoping that the management upheavals are over—and that they can get on with their work. One hot project is the development of an artificial niche to sustain stem cells by Haylock and Susie Nilsson at the center's headquarters here. Researchers have had little success at coaxing adult stem cells to remain stem cells once isolated in culture, a major limitation to producing big batches of cells. In their original source tissue, however, stem cells are renewed. Part of the explanation, researchers have long realized, is that stem cells are cocooned in a niche, where they are regulated by proteins embedded in a matrix or secreted by cells. Artificial niches should transform the culturing of adult and embryonic stem cells from a black art to a robust, scaleable technique, says Nilsson.

    Haylock and Nilsson are trying to build an artificial stem cell niche using a polymer scaffolding affixed with key signaling molecules such as osteopontin and hyaluronic acid. “The center has put us in contact with surface engineers, surface chemists, polymer chemists,” Nilsson says. Haylock credits Livesey for bridging biologists and engineers. “He was the sole person who understood the interactions with the engineering disciples. He should be applauded for his vision,” says Haylock.

    “The real issues the center faces are not about its past but about its future,” says Collins. ASCC's fate should soon be clear. In the meantime, says Haylock, “We just shut the door on the politics and focus on the science. That's where the buzz is.”

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