# News this Week

Science  04 May 2007:
Vol. 316, Issue 5825, pp. 672
1. U.S. SCIENCE POLICY

# Congress Gives Rousing Support to Cluster of Innovation Bills

1. Jeffrey Mervis

The U.S. Senate has a reputation for looking at the big picture, the House for attending to details. Both bodies followed that pattern last week, passing a collection of bills that would significantly boost the government's support for research and training. The White House opposes most of the bills, which draw heavily from a 2005 National Academies' report, but the lopsided margins of victory suggest that they could become law if the Democratic-controlled Congress decides to make them a priority.

The Senate bill, called the America COMPETES Act (S. 761), is the more impressive accomplishment. The acronym sums up its sweeping nature: Creating Opportunities to Meaningfully Promote Excellence in Technology, Education, and Science. Nearly 2 years in the making, it is a bipartisan measure with 63 co-sponsors and the support of the chairs and ranking members of three committees with jurisdiction over most of civilian science and education across several federal agencies. “This legislation represents the best way for our country to keep its brainpower advantage, and our brainpower advantage is the way we keep good-paying jobs from going overseas,” said Senator Lamar Alexander (R-TN), after the 25 April vote, immodestly calling it “the biggest piece of legislation in Congress this year.”

The bill, which passed by a margin of 88 to 8, would authorize a 5-year doubling of the National Science Foundation's (NSF's) budget and lesser but still substantial hikes for the Off ice of Science at the Department of Energy (DOE) and the National Institute of Standards and Technology (NIST). It would fund new and expanded education and training programs at NSF, DOE, and the Department of Education at all levels, from elementary through graduate schools. In a statement before the vote opposing passage, the White House budget office called the authorization levels “excessive and inappropriate” and complained about the “unnecessary bureaucracy and education programs.” The Administration has proposed a 10-year budget doubling for NSF, DOE science, and NIST's in-house labs in its American Competitiveness Initiative (Science, 17 February 2006, p. 929).

Meanwhile, the House is moving several bills that are part of a package the Democrats call their Innovation Agenda; it predates the president's proposal and also relies heavily on the academies' Rising Above the Gathering Storm report (Science, 21 October 2005, p. 423). Last week, with fewer than two dozen dissenters, the House passed H.R. 362, which would boost NSF programs to train more science and math teachers and encourage more students to pursue research careers, and H.R. 363, which increases support for young investigators. This week, it was expected to pass reauthorization bills for NSF and NIST. Waiting in the wings is a bill to create a nimble energy research entity modeled after the Pentagon's Defense Advanced Research Projects Agency. The piecemeal legislation is consistent with the philosophy of the chair of the House Science and Technology Committee, Representative Bart Gordon (D-TN), who believes that more tightly focused bills stand a better chance of passage in the House.

The Senate is not expected to take up the House bills, meaning that the next steps could be a conference committee appointed by Senate Majority Leader Harry Reid (D-NV) and House Speaker Nancy Pelosi (D-CA). But the final format of such legislation is hazy at this point. “Given the overwhelming support for these bills, if they really want to make it happen, they can do it,” says one agency lobbyist. “But how do they craft the right package? That's the question.”

2. RESEARCH FUNDING

# European Research Council Deluged After First Call for Proposals

1. Martin Enserink

When the leaders of the European Research Council (ERC) started planning their first call for proposals last year, they expected an enthusiastic response from scientists seeking a slice of the €290 million in research funds—perhaps as many as 3000 applications for the 200 to 250 grants the ERC planned to give out to young researchers in 2007. Instead, when the deadline for the first round had passed last week, 9167 proposals had flooded in—an “astonishing” number, says Helga Nowotny, vice-chair of the ERC's scientific council.

Although a clear vote of confidence for the new funding agency, Nowotny says, the response by Europe's scientists also poses an acute problem: how to winnow out more than 97.5% of the proposals on a very tight timetable. “It's horrendous,” says Frank Gannon, the outgoing head of the European Molecular Biology Organization in Heidelberg, Germany. “Numbers like that are very hard to handle for any funding agency.”

The ERC will give out basic research grants to individual scientists, based only on the quality of their grant proposal. That's a novelty for the E.U., which has traditionally funded large networks of labs and companies across the continent to do mostly applied research.

The deluge won't compromise the review process, promises ERC Chair Fotis Kafatos of Imperial College London. The agency is enlisting hundreds of extra reviewers to provide written analyses of grants to the 20 review panels originally planned.

A possible downside of the mammoth number of proposals is that a very low success rate may discourage future applicants. But Nowotny points out that a scientist's investment of time—preparing a four-page proposal—is relatively small for the payoff. The review panels will be asked to pare down the applicants by more than 90% during meetings in June, so that those who make it through have between a 30% and 50% chance during the second stage, which includes writing a more detailed proposal and possibly interviews. Meanwhile, the ERC is preparing to launch a second funding round for advanced researchers later this year.

The huge interest in this first round sends a clear message to European politicians, says Peter Nijkamp, chair of the Dutch funding agency NWO: The ERC was sorely needed, but its budget—€7.5 billion for 2007 to 2013—is “absolutely insufficient.”

3. ASTROPHYSICS

# Deep Ringing of the Sun Hints at a Speedy Core

1. Richard A. Kerr

How do you peer through a star's worth of multimillion-degree roiling plasma to grasp the innermost workings of the sun? Very steadily, for a very long time, from very far away, it turns out.

Researchers report online in Science this week (www.sciencemag.org/cgi/content/abstract/1140598) their analysis of 10 years of continuous observation from a perch just sunward of Earth. They believe they are the first to reliably detect excruciatingly subtle vibrations in the solar surface coming from the sun's very core. Using the newly identified oscillations as a probe, they have found strong hints that the core is rotating faster than the rest of the sun. Such extra zip may be left over from the sun's formation.

“People have been looking for these [vibrations] for 30 years,” says solar physicist John Harvey of the National Solar Observatory in Tucson, Arizona. If confirmed, he says, the discovery is “going to be one of the big milestones of helioseismology”—the field in which researchers study the solar interior using the sun's bell-like ringing set off by internal churnings.

Probing the shallow solar interior has long been routine, but helioseismologists had never before detected “g modes” of vibration. Some of these long-sought waves pass through the tiny solar core where fusion reactions power our star. Little wonder they've eluded searchers. The g (for gravity) mode vibrations probably originate when down-rushing plumes pummel the stable deep interior. Some of the resulting waves continue downward and pass through the core but eventually reach the surface. By then, however, they are feeble, raising or lowering the surface at only a few millimeters per second.

To detect such subtle breathing of the surface, helioseismologists Rafael García of the Astrophysics Service of the French Atomic Energy Commission in Saclay and colleagues went to the Global Oscillation at Low Frequencies (GOLF) instrument onboard the Solar and Heliospheric Observatory. GOLF had been staring at the sun for 10 years, measuring how the entire solar disk rises and falls by examining sunlight for any Doppler shift. According to solar theory, some g modes should be raising and lowering a whole hemisphere every few hours or so amid the far stronger, shallowly propagating p (soundlike) modes and noise of the turbulent sun.

Relying on the long observational record and the distinctive spacing of g-mode periods, García and his colleagues report that they have detected the signature of g modes in GOLF data, with a likelihood of 99.5% or better. With less confidence, by comparing the observations with model g modes, they see signs that the core is spinning three to five times faster than the overlying middle layer of the sun. That extra spin could be lingering from the sun's formation, while the outer layers have lost much of their rotational momentum over the eons to the mass of solar wind particles flung into space.

García and his colleagues “are likely to have seen an interesting pattern of g modes,” says Juri Toomre of the University of Colorado, Boulder. “The trouble is there are not enough constraints to make very many inferences” about the core. Many poorly known properties of the core affect the character of g modes, he notes. “It's just a very tough game.” To score more points in the g-mode game, researchers are looking to replace the aging GOLF instrument with an even keener eye in the sky.

4. U.S. SCIENCE FUNDING

# DOE Cures Pork Project With Peer Review

1. Eli Kintisch

Long dependent on the patronage of a powerful U.S. senator, a New Mexico neuroimaging center has discovered a new route to government research dollars: the front door at the Department of Energy (DOE). But the way it got there has left some lawmakers with the impression that the center is still benefiting from its congressional patron.

Like other facilities with special ties to Capitol Hill, the Mental Illness and Neuroscience Discovery (MIND) Institute at the University of New Mexico in Albuquerque began this year with a daunting challenge. The final 2007 federal budget was largely devoid of earmarks (see graph): money that lawmakers designate for pet projects, bypassing an agency's competitive funding procedures. The MIND Institute has received roughly $10 million a year from DOE since 1999 courtesy of Senator Pete Domenici (R-NM), a longtime chair or ranking member of the Senate panel that oversees DOE's Office of Science and an outspoken advocate of mental health research. But this spring, for the first time, the MIND Institute successfully ran the gauntlet of DOE's peer-review system and is about to receive$7 million for neuroimaging studies on schizophrenia, addiction, and criminal behavior. The MIND Institute is one of only a handful of institutions to avail themselves of an unusual opportunity: After Congress stripped earmarks from the 2007 budget, DOE said it would be willing to review proposals from institutions that were in line to receive earmarked funds. Even before DOE officially announced that offer, however, the MIND Institute had already submitted a 700-page proposal. DOE spokesperson Aimee Whitelaw says three others have applied, and one is pending.

Created in 1999, the center has shared a large fraction of each year's earmark with its partners, including Massachusetts General Hospital in Boston. In 2003, the MIND Institute moved into the new Pete and Nancy Domenici Hall, and 2 years later, Domenici said he hoped that the MIND Institute was “moving in a direction of self-sufficiency.” Indeed, last year the institute won a $2.2 million competitive grant from the Pentagon's Defense Advanced Research Projects Agency to study accelerated learning; it also hired two researchers who had funding from the National Institutes of Health. Staffers say the money has been put to good use, and outsiders generally agree. Neuroscientist Kent Kiehl says that distributed computing facilities worthy of “a Fortune-500 company” helped attract him from Yale University. The ability to pool subjects drawn from the MIND Institute's network of partners, he adds, will enhance his research with magnetic resonance imaging to diagnose psychotic disorders. Neuroscientist Don Rojas of the University of Colorado, Denver, unaffiliated with the MIND Institute, sees “a lot of potential” in the institute's solid infrastructure and personnel. “But they don't have a measurable scientific product yet,” he says. Despite the institute's positive steps toward independence, Domenici sought$12 million for it in the 2007 spending bill moving through Congress last year. When the new Democratic majority decided in December to remove all domestic earmarks from the final bill, MIND Institute staffers immediately sought guidance from DOE staffers and Domenici's office. In January, DOE's Michael Viola visited the institute. “He told us what the format should be, what they expected,” says institute science director Vincent Clark. On 30 January, says MIND Institute Director John Rasure, his team submitted its proposal.

That rapid response gave the institute a jump on the competition. On 2 February, DOE circulated an internal memo explaining that the agency would fund “meritorious proposals” from earmark recipients and asking staff to look out for such projects. On 14 February, Senator John McCain (R-AZ), a critic of such pork-barrel projects, entered the memo into the Congressional Record as part of a statement trumpeting the lack of earmarks in 2007.

After House members of DOE's spending panel learned of the MIND Institute application, they scolded Raymond Orbach, director of DOE's Office of Science, for not telling them directly about DOE's new policy. “So what we're all getting at here is fairness,” said Representative David Hobson (R-OH), ranking member of the House Energy and Water spending panel, at a 14 March hearing. Representative Mike Simpson (R-ID) said the Administration's “unwilling[ness] to have transparency” on DOE's earmarks was “hypocrisy” given the White House's stated aversion to pork. Six days after the hearing, Orbach sent a letter to the roughly 125 institutions that received earmarked DOE funds in 2006 informing them of the memo. “Everyone was treated the same,” says Whitelaw of the process.

It's not clear how many earmarks will make it into the 2008 budget wending its way through Congress. A House appropriations aide says that there's been an avalanche of requests, and House Appropriations Chair David Obey (D-WI) is considering omitting them again. But few expect Domenici and Senator Robert Byrd (D-WV), chair of the Senate spending panel and a prodigious earmarker, to give up without a fight.

5. SPACE SCIENCE

# European Union Outlines Vision for Unifying Space Policy

1. Daniel Clery

The European Union (E.U.) doesn't have its own astronauts, operate any satellites, or launch any rockets. The E.U. doesn't even have a space research center, but last week, after 2 years of deliberation, it revealed its much-heralded space policy. The aim is to bring more coordination and coherence to Europe's space programs, which are currently spread among national agencies and the European Space Agency (ESA). European space scientists, however, are underwhelmed. “This will change very little for space science in Europe because there is no more money,” says Roger Bonnet, director of the International Space Science Institute in Bern, Switzerland, and former head of science at ESA.

The E.U. is a major consumer of earth-observation data and sees space industry as a strategic arena in which European companies can compete worldwide. Yet it has had little direct influence on ESA's programs or the activities of countries such as France, Germany, and Italy that maintain active national space agencies. ESA's modus operandi doesn't necessarily take into account the E.U.'s wider political, social, and economic goals. Moreover, ESA's 17 members include some that are not part of the E.U., whereas the E.U. has 27 member states.

Despite this difference, E.U. officials and ESA Director General Jean-Jacques Dordain agreed in 2005 to develop a Europe-wide space policy. The document revealed last week—which must still be ratified by ESA's Council and E.U. ministers during May—calls for greater coordination to meet shared objectives and avoid duplication. It also encourages synergy between civil and military space efforts and mandates the E.U., ESA, and national agencies to find funding for two key programs: the Galileo navigation satellites, and an earth-observing system called Global Monitoring for Environment and Security (GMES).

GMES aims to provide European policymakers and other civil users with continuous data on, for example, land use, pollution, floods, forest fires, and earthquake damage. Günter Verheugen, E.U. vice-president responsible for enterprise and industry, has said that this system will likely cost €2.4 billion. Galileo will be a commercial rival to the U.S. Global Positioning System (Science, 23 December 2005, p. 1893). The E.U. is asking industry to pay for two-thirds of the €2.1 billion cost of building the system and all of the operating costs.

Bonnet calls these two projects test cases for the new E.U. space policy. “Until we see success in these projects, the policy is no more than a piece of paper,” he says. Challenges await. The consortium of eight companies that the E.U. chose to build and operate the system has bickered long and hard over the division of work and missed deadlines. Meanwhile, Russia is rejuvenating its Glonass navigation system, and China appears to be building one as well—all unwanted competition for Galileo.

Some space researchers are concerned about the increasingly close relationship between ESA and the E.U. According to ESA rules, science spending is ring-fenced, and all members must contribute to it. That wouldn't necessarily be the case if ESA became an E.U. institution, says Alan Smith, director of the U.K.'s Mullard Space Science Laboratory. “A lot depends on how ESA sees its future,” he says.

6. STEM EDUCATION

# Report Urges More Coordination to Improve Science and Math

1. Yudhijit Bhattacharjee

Many U.S. educators and policy experts believe that the country's decentralized management of education by state and local government bodies is hampering nationwide efforts to improve science, technology, engineering, and math (STEM) education. But a new draft plan, drawn up by the board that oversees the National Science Foundation, suggests a way to get around that problem without abandoning 2 centuries of local control over schools.

The proposal from the National Science Board, requested by the previous Congress, recommends creating a federally chartered body with representatives from the states, the federal government, and the education and business communities. The National Council on STEM Education would coordinate initiatives across federal agencies and work with the states to help them adopt a core set of content standards, link state assessments to those national standards, and create a system of national certification for STEM teachers.

The proposal has come from a blue-ribbon commission, co-chaired by physics Nobelist Leon Lederman, which the board set up last year to tackle the issue (Science, 7 April 2006, p. 45). “There is a serious disconnect between the different elements of the school system in this country, with each of 15,000 school boards doing their own thing,” says Steve Beering, chair of the board. “The commission felt that there was a clear need for a nationally coordinated effort to bring about some standardization in content and teaching.”

The idea has drawn mixed reactions. “Anything at the federal level that would help the states improve science and math education is a good idea,” says Jodi Peterson of the National Science Teachers Association (NSTA). But others worry that the new organization will simply increase the current welter of agencies and organizations active on the issue. “It will lead to more bureaucracy, more meetings, and more talk,” predicts Chester Finn Jr., president of the Fordham Institute, an education nonprofit based in Washington, D.C.

“We're not talking about establishing a new federal agency,” responds Jo Anne Vasquez, a University of Arizona, Tucson, education professor and board member who is a former NSTA president. “And we are well aware that the states and local school districts are ultimately responsible for education.” The proposed body would be a nerve center for activity at the state level, she says, providing expertise and guidance in the same way that the National Academies provide advice to the federal government.

Selling the idea to state officials will also be tough because of fears that it could undermine their authority. “We are in favor of better coordination between federal agencies and better coordination of educational activities within each state,” says Joan Wodiska of the National Governors Association (NGA) in Washington, D.C. But states are wary of anything that smacks of a top-down approach, including a national curriculum. Besides, states are already working together to improve STEM education and economic competitiveness, Wodiska says, pointing to an ongoing NGA initiative known as Innovation America that is aimed at getting states to share best practices.

Proponents admit that it will take time for everyone to get comfortable with the concept. “We expect many to say: 'Oh, it's so difficult' [to reform education nationally],” says Lederman. “We know it's difficult, but it's needed.”

7. GENETIC DISCRIMINATION

# Long-Awaited Genetic Nondiscrimination Bill Headed for Easy Passage

1. Constance Holden

Twelve years after it was first introduced in the U.S. House of Representatives, a genetic nondiscrimination bill finally appears to be on its way to becoming law.

The House passed H.R. 493, the Genetic Information Nondiscrimination Act (GINA), on 25 April by a vote of 420 to 3. Although action on a Senate version of the bill has not yet been scheduled, the Senate unanimously passed versions of GINA in 2003 and 2005, and President George W. Bush has announced his support of the measure. The sticking point had always been in the House, where the Republican leadership, reflecting opposition from some business groups, blocked the bill from coming to a vote. With the Republicans swept out of power in the 2006 elections, the bill moved quickly to the floor and is expected to pass the Senate this month.

GINA bans group health plans and insurance companies from denying coverage or charging higher premiums to healthy individuals based on genetic information. It also applies to employers, preventing the use of genetic information in hiring, firing, or job-placement decisions.

In public opinion polls over the years, a growing majority of respondents have indicated a desire for the legislation. Now, said Representative Louise M. Slaughter (D-NY), chief sponsor of the bill, GINA “will allow us to realize the tremendous potential of genetic research without jeopardizing one of the most fundamental privacies that can be imagined.”

Advocates of the bill claim that many people are afraid to undergo genetic tests—for instance, to detect a mutation that increases risk of breast cancer—for fear that insurers or employers will discriminate against them based on that information. And a 2000 survey of genetic counselors indicated that, for the same reason, more than half would not submit charges for genetic tests to insurance companies.

Supporters of the legislation cite instances of discrimination based on confusion about genetic information, such as denial of jobs to healthy African Americans who carried one copy of the sickle cell anemia gene. In a recent case, Slaughter reported, a mother who has α1 anti-trypsin disease was denied health insurance for her two children based on their carrier status, even though they were not affected by the disease.

The threat of genetic discrimination has also hindered research, said Francis Collins, director of the National Human Genome Research Institute in Bethesda, Maryland, at a House hearing in March. “Unless Americans are convinced that the information will not be used against them, the era of personalized medicine will never come to pass,” he said.

Until now, the privacy of genetic information has been protected by “a largely untested patchwork” of federal and state regulations, according to the Genetics and Public Policy Center (GPPC) at Johns Hopkins University in Baltimore, Maryland. GPPC head Kathy Hudson says that the main resistance to GINA has come from groups such as the Chamber of Commerce concerned with infringements on employers' decision-making freedom. But in the end, advocates prevailed. As Hudson notes, “it's pretty hard to vote for discrimination.”

8. RESEARCH SAFETY

# Inquest Flags Little-Known Danger of High-Containment Labs

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

MELBOURNE, AUSTRALIA—A coroner issued a stern rebuke to Australia's national science agency last week, accusing the Commonwealth Scientific and Industrial Research Organisation (CSIRO) of “complacency” in the death of a senior technician in 2001. CSIRO officials say they have tightened laboratory safety since the accident and hope that the researcher's death will serve as a warning to high-security biology labs around the world.

The tragedy unfolded on the afternoon of 10 December 2001, when Set Van Nguyen, 44, entered a containment room at CSIRO's Australian Animal Health Laboratory (AAHL) in Geelong, Victoria. The chamber houses lethal pathogens such as bat-borne lyssavirus and is kept under low pressure to ensure that air flows inward. In the days leading up to Nguyen's death, the containment room had been malfunctioning, according to findings from an inquest released last week by Geelong coroner Audrey Jamieson. For roughly 4 days, sensors registered diminishing levels of oxygen in the room, and a liquid-nitrogen tank inside was leaking, the inquest found. AAHL made two announcements over its PA system about the breakdown and posted warning signs outside the airlock, says AAHL biosafety officer Gordon Abraham. Adds AAHL Director Martyn Jeggo, “We thought we had a truly fail-safe system with bells, flashing alarms, and meters giving oxygen readings.”

Nguyen was no novice: A 13-year CSIRO veteran, part of his job was to train other staff members how to use the airlock system, Jeggo says. Around 4:15 p.m., Nguyen entered the chamber, apparently intending to collect a specimen from the cooler and to post more warning signs, says Abraham. A digital readout outside the chamber indicated that oxygen levels inside were 0.03%. After Nguyen's alarmed wife showed up at the lab early the next morning, AAHL staff found his body in the airlock. According to the coroner's report, he was still clutching the empty vial in his right hand with the warning signs on the floor next to him.

Jamieson ruled that Nguyen died of acute oxygen deficiency. He may have passed out instantly, says Jeggo, adding that “most people including myself” may not have been aware of the risk of rapid loss of consciousness. “I remember the adage: You can live without oxygen for 3 minutes, without water for 3 days, and without food for 3 weeks. I'd change that,” says Abraham. “Without oxygen, you go unconscious in 3 seconds and die within 3 minutes.”

In her report on the inquest, held last year, Jamieson said that Nguyen's death “can only be attributed to a level of complacency” at CSIRO. Although not singling out any individual for blame, she criticized AAHL for, among other things, failing to educate staff about the risks of nitrogen and not keeping better track of staff.

The findings are “probably an accurate reflection of the lab at that time,” says CSIRO Chief Executive Geoff Garrett. Since Nguyen's death, he notes, CSIRO has “implemented serious interventions in health and safety” at AAHL and 50 other facilities. “We need to engineer out any risk of human error,” says Jeggo. Now at AAHL, containment doors lock down if oxygen levels fall below 19.5%, and electronic cards ensure that every employee can be located while at work.

In an e-mail to all CSIRO staff after the coroner's report, Garrett expressed “deep condolences” to Nguyen's family and sought to draw a line under the affair. “We have learned several important lessons from this tragedy to help us ensure that a similar event should never happen again,” he said.

9. ECOLOGY

# A World Without Corals?

1. Richard Stone

Besieged by pathogens, predators, and people, the “rainforests of the sea” may soon face their ultimate foe: rising ocean acidity driven by CO2 emissions

KHURA BURI, THAILAND—In the shallow waters off Lan Island in the Andaman Sea, Kim Obermeyer kicks his flippers and glides over a silent graveyard. Scattered below are shards of staghorn and other branching corals, shattered in fragments that look like detached finger bones. The conservation biologist swims farther out to sea, darts to the bottom, and peers under an overturned Porites coral head the size of a Volkswagen Beetle. Obermeyer points to a brown ribbon underneath: a ragged colony soaking up just enough sun to have survived the tsunami that struck on 26 December 2004.

As a horrific tragedy unfolded on shore that day, ecosystems below the ocean's surface were getting hammered. Across Southeast Asia, the titanic waves ripped apart shallow reefs and buried others in silt. But tsunamis are not the worst threat. The main menaces are largely human-wrought: from divers clumsily breaking off chunks of coral to mass die-offs and bleaching of coral triggered by spikes in ocean temperatures. Last month, the Intergovernmental Panel on Climate Change (IPCC) forecast “more frequent coral bleaching events and widespread mortality” with average global temperature increases of 1° to 3°C.

Surveys suggest that 20% of the reefs on Earth, the largest living structures on the planet, have been destroyed in the past few decades. Another 50% are ailing or verging on collapse. “Reefs are likely to witness a significant ecological crisis in the coming half-century—because of us,” says coral specialist Camilo Mora of Dalhousie University in Halifax, Canada.

The decline of coral reefs may have staggering consequences. Globally, reefs generate about $30 billion per year in fishing, tourism, and protection to coasts from storm surges, says Mora. Although reefs cover a minuscule fraction (0.1%) of seabed, they are second only to rainforests in biodiversity, sheltering or nourishing up to 9 million species—a third of all known marine life forms—including 4000 kinds of fish. “To predict that reefs will change dramatically across the globe in the matter of a single generation should keep people up at night,” says Ove Hoegh-Guldberg, director of the Centre for Marine Studies at the University of Queensland in St. Lucia, Australia. There are a few rays of light in this bleak seascape. Attempts to rehabilitate tsunami-damaged reefs are showing promising results. Some reefs blighted by bleaching have mounted spectacular comebacks. And efforts to limit fishing and human activity have paid dividends in healthier reefs and revived local fisheries. Over the past decade, hundreds of marine protected areas have been established to safeguard reefs, including innovative MPAs in Palau designed to help corals bounce back after bleaching (see sidebar, p. 680). Yet these gains could be erased by what's shaping up as the gravest threat of all. As the oceans soak up more and more of the carbon dioxide that humans pump into the atmosphere, marine chemistry is changing. CO2 emissions “have the potential to create chemical conditions in the ocean that have not occurred since the dinosaurs became extinct,” says ecologist Kenneth Caldeira of the Carnegie Institution of Washington in Palo Alto, California. Dissolved in water, CO2 becomes carbonic acid. Caldeira coined a term for this process in a paper in 2003: “ocean acidification.” By midcentury, ocean pH could dip so low that corals would be unable to form their calcium carbonate skeletons. “Acidification is the big elephant in the room,” says Terence Hughes, director of the Australian Research Council's Centre of Excellence for Coral Reef Studies at James Cook University in Townsville, Australia. Reef building would grind to a halt, with grievous implications. If CO2 emissions are not curtailed, Hughes predicts, “we'll eventually see reefs dominated by sea anemones and algae.” Put another way, “soon we'll be having jellyfish and chips,” says biologist Michael Kendall of the Plymouth Marine Laboratory in the United Kingdom. In the darkest scenarios, most corals will be toast. ## A multiheaded monster As coral reefs slip toward chronic frailty, a picture of what this means to the world has begun to emerge. Coral scientists, backed by an army of snorkeling and diving volunteers, have put a watch on critical reefs among the nearly 300,000 square kilometers charted to date. Hidden gems continue to come to light, including a giant deep-water reef in turbid waters off northern Australia. “Not much is known about the reef because nobody wants to swim in that area. It's infested with crocodiles,” says oceanographer Alan Strong, senior consultant to the U.S. National Oceanic and Atmospheric Administration's (NOAA's) Coral Reef Watch. A recurring theme of this heightened scrutiny is that reefs are vulnerable on many fronts. A March 2005 earthquake off Indonesia, for example, was as brutal as the 2004 tsunami, lifting some reefs clear out of the water (Science, 20 October 2006, p. 406). Corals are susceptible to pathogens and predators, too. The crown-of-thorns starfish, a periodic invader, denudes coral outcroppings with the efficiency of a slash-and-burn farmer. Meanwhile, corals are perpetually besieged by filamentous algae, which are held in check by fish that nibble at them. Overfishing can tilt the balance, as can sewage or agricultural runoff, which infuse seawater with algae-feeding nutrients. These abuses, along with coastal development, “are having fantastically large and negative impacts on reefs around the world,” says John Pandolfi, a coral reef expert at the University of Queensland in Brisbane, Australia. The latest and perhaps biggest present danger for reefs is bleaching. When sea surface temperatures exceed their normal summer high by 1°C or more for a few weeks running, coral polyps, for reasons not entirely understood, expel their zooxanthellae, the symbiotic algae that lend corals color and provide nutrients. The polyps turn pale and starve. “If they don't get their zooxanthellae back in a month or so, they die,” says Obermeyer. The dangers of bleaching came to the fore in 1998, when a potent one-two climate punch—a strong El Niño warming in central tropical Pacific waters, followed by a La Niña that heated western Pacific regions—killed 16% of living corals worldwide (Science, 27 October 2000, p. 682). Some reefs have rallied from severe bleaching—recently and dramatically, off Darwin Island in the Galápagos. “We'd given up on the Galápagos” after a 1982-83 bleaching event annihilated most of the archipelago's reefs, says Strong. Now, he says, “it seems to be really coming back.” However, many bleached reefs are still sickly. At least half of those destroyed in 1998 have not recovered, according to the authoritative Status of Coral Reefs of the World: 2004, compiled by the Global Coral Reef Monitoring Network (GCRMN). The catastrophic 1998 bleaching, and regional occurrences since then, highlight the vulnerability of reefs to global warming. “That's when we realized that corals could be a kind of canary in a coal mine,” says Jeremy Goldberg, co-author of a GCRMN report on tsunami-inflicted reef damage. Delicate staghorn and elkhorn corals, for example, were listed as threatened in the Caribbean in May 2006 under the U.S. Endangered Species Act. “Branching corals that are sensitive to bleaching might disappear,” warns reef ecologist Thamasak Yeemin of Ramkhamhaeng University in Bangkok. Some reefs are more tolerant to bleaching. However, says Hoegh-Guldberg, “the movement toward hardier communities of fewer coral species is hardly a 'win.'” Coral abundance is still plummeting, and even resistant corals may succumb in a warmer world, he says. “As climate change accelerates, we will lose an increasing number of coral species, making ecosystems less resilient to other pressures.” A case in point is the widespread bleaching in the Caribbean Sea in 2005-06. At one reef off St. John, part of the U.S. Virgin Islands, “before people knew it, a disease infected the coral that had survived the bleaching. What was left was totally wiped out,” Strong says. “You can see how this gets to be a multiheaded monster.” NOAA and U.S. National Park Service scientists are now searching for clues to why some corals survived whereas others perished. In an attempt to boost reef survival, governments have been setting up MPAs, which range from free-for-all recreational parks to no-take zones that bar fishing. Fewer than 3% of the world's reefs lie inside no-take MPAs, says Mora. Many reefs are being fished out. Raising the specter of a pending food crisis, a recent study found that 27 of 49 island countries are exploiting their reef fisheries in an unsustainable way, reports a team led by Nicholas Dulvy of the Centre for Environment, Fisheries, and Aquaculture Science in Lowestoft, U.K., in the 3 April issue of Current Biology. Lax enforcement and lack of local buy-in have undercut many MPAs. “If communities are not involved, they are very unlikely to support an MPA imposed on them,” says Obermeyer, coordinator for Reef Check Thailand. With volunteers from Reef Check and a second nonprofit, Earthwatch, Obermeyer endeavors to involve villagers—and here near Khura Buri, the Ranong Coastal Resources Research Center of Kasetsart University—in reef monitoring. “This is the only way to succeed,” he says. MPAs and measures such as stanching sewage and runoff cannot prevent bleaching. But resilience—the capacity of a reef to absorb recurrent bleaching and still function—can be enhanced, Hughes says. In 2002, more than half of Australia's 40,000-square-kilometer Great Barrier Reef bleached. Two years later, Australia created the world's largest no-take zones, extending fishing bans covering 4.6% of the reef to more than 33%. “This initiative provides real insurance cover against the inevitable impacts of climate change,” says Hoegh-Guldberg. To test this approach, Hughes and colleagues caged some reef sections and left others open to grazing by parrot-fish, known by their fused, beaklike teeth. Polyps reestablished on open reef three times faster than on caged sections, they report in the 20 February issue of Current Biology. The study shows that reef management after bleaching “has a big effect on the recovery rate,” Hoegh-Guldberg says. But the strategy works only in the short run; nations must move rapidly to stem greenhouse gas emissions, he says. “It is next to useless not to do the two things together.” ## A mortal blow? Until bleaching reared its head, many experts viewed rising sea levels as the chief peril of global warming for coral—and a relatively toothless one at that. “We thought reefs would respond by just growing higher,” says Strong. “Nobody was talking about changing sea chemistry.” Then researchers came to the creeping realization that rising ocean acidity is likely to throw a spanner in coral physiology. The threat is glaringly simple. Currently, ocean pH hovers around 8.1. Carbon dioxide absorbed into the water column lowers the pH, and as it falls, fewer carbonate ions are available for shell-building critters to grab. Even in present conditions, corals are fighting an uphill battle: Erosion removes 80% of the calcium carbonate laid down. Acidification will accelerate that process as rising carbonic acid levels deplete carbonate. Eventually, corals, plankton, and other organisms will fail to form skeletons. And coral skeletons are to reefs what girders are to skyscrapers. “You have a potential world in which reefs and the limestone frameworks they have built are in net erosion,” says Hoegh-Guldberg. IPCC scenarios of global emissions and ocean circulation indicate that by midcentury, atmospheric CO2 levels could reach more than 500 parts per million, and near the end of the century they could be above 800 ppm. The latter figure would decrease surface water pH by roughly 0.4 units, slashing carbonate ion concentration by half, paleocoral expert C. Mark Eakin, coordinator of NOAA's Coral Reef Watch, testified last month at a hearing in the U.S. House of Representatives. Ocean pH would be “lower than it has been for more than 20 million years,” he said. And that does not factor in possible acidification from carbon-sequestration schemes now being considered. Some coral species facing their acid test may become shape shifters to avoid extinction. New findings indicate that corals can survive acidic conditions in a sea anemone-like form and resume skeleton-building when returned to normal marine conditions (Science, 30 March, p. 1811). However, by pH 7.9, says Caldeira, “there would be a good chance reefs would be gone.” The potential for an acid-induced coral cataclysm has cast a pall on the tight-knit community of reef specialists. “The reality of coral reefs is very dark, and it is very easy for people to judge coral reef scientists as pessimists,” says Mora. “We're becoming alarmist,” adds Strong—for good reason, he insists. “How are reefs going to handle acidification? It's not like sewage or runoff, where you may be able to just turn off the spigot.” Queensland's Pandolfi, however, argues that it's “too early to make really definitive doom-and-gloom statements.” No one disputes that urgent action on greenhouse gas emissions is essential. “We could still have vibrant reefs in 50 years time,” Hughes says. But these will not be the reefs we know today. “They will be dominated by a different suite of species,” says Hughes, who notes that the shakedown is already under way. More likely, steps to rein in emissions will be too little, too late—and the world will have to brace for the loss of reefs. In Southeast Asia, says Hoegh-Guldberg, the threat of millions of people losing their livelihoods must be factored into policy planning. Coastal dwellings throughout the tropics will have to be strengthened against higher waves. Then there is the intangible, aesthetic deprivation if coral reefs wither and wink out. “Without their sheer beauty,” Hughes says, “the world would be an impoverished place.” 10. ECOLOGY # Fractured Paradise 1. Richard Stone PHUKET, THAILAND—Like thousands of tourists who flock to the chic resort island of Phuket in southern Thailand, marine biologist Niphon Phongsuwan recently spent a weekend under the waves, taking in the region's breathtaking coral reefs. Unlike the tourists, Niphon had an extra reason to enjoy the view: His innovative attempt to rehabilitate tsunami-damaged reefs is showing remarkable progress. Two of the most-savaged reefs lie off Phuket's Paradise Beach and Lolana Bay on nearby Phi Phi Island. During surveys carried out a few days after the tsunami, Niphon and his colleagues at the Phuket Marine Biological Center discovered the shallow seabed at Paradise and Lolana littered with pieces of branching corals, particularly staghorn and other members of the Acropora genus. Realizing that the polyps would be abraded to death in the rough-and-tumble waters, Niphon's group gathered up hundreds of Acropora fragments in a bid to save them. Aboard a research vessel, the team glued the coral fragments into holes drilled in concrete cinder blocks. They joined blocks with steel bars to help the structure weather strong currents and placed them in various configurations in either shallow reef flats, less than 2 meters deep at low tide, or on reef slopes about 7 meters deep. Blocks in the reef flats—natural Acropora habitat—were battered by waves, and most polyps died. But corals transplanted to reef slopes at Lolana Bay thrived and have grown at a rate equivalent to naturally occurring Phuket corals, Niphon says. The “unexpected” findings, he says, suggest that Acropora “can adapt well to a new environmental setting.” The hope is that the growing thickets of branching coral will provide a breeding population: seed stock for polyps that mend damaged reefs and pioneer new ones. The coral growth over 2 years is “impressive,” says oceanographer Alan Strong, senior consultant to the U.S. National Oceanic and Atmospheric Administration's Coral Reef Watch. For Acropora, he says, the low-tech cinder blocks may offer a cheap alternative to the leading artificial reef product: Reef Balls, molded concrete forms that cost as much as several thousand dollars and range up to 2 meters in girth. Strong and others caution that although coral reefs can be rehabilitated, they cannot be built from scratch. “No one has ever reconstituted a reef,” says Hughes. And some experts wonder whether reef rehab is worth the effort at all, as it addresses a symptom of decline, not the cause. “Inevitably, this kind of work is like treating cancer with a Band-Aid,” says John Pandolfi, a coral reef expert at the University of Queensland in Brisbane, Australia. “It makes us feel good, but our money is better spent elsewhere.” 11. ECOLOGY # Palau Combats Coral Bleaching 1. Christopher Pala* 1. Christopher Pala is a writer based in Honolulu, Hawaii. BABELDOAB, PALAU—A giant clam's purplish-green intake valve, big enough to swallow a fist, snaps shut when a diver drifts close. The magnificent meter-wide mollusk in Ebiil Channel is a symbol of survival, whereas a beige, 2-meter-wide table coral nearby is a vivid example of rapid recovery. In the summer of 1998, unusually warm ocean temperatures killed a third of the reefs ringing this tiny archipelago in the western Pacific. But here in the Ebiil Channel Conservation Area off Babeldoab, Palau's main island, underwater denizens have roared back to life with exceptional vigor. Ebiil's inspiring comeback is the basis for an ambitious experiment. The Nature Conservancy, a U.S. nonprofit, is helping Palau establish the world's first national network of marine protected areas (MPAs) aimed at thwarting bleaching, a phenomenon in which warm ocean waters trigger corals to expel symbiotic algae and starve (see main text). Some corals can resist or recover from bleaching. The Palau network intends to safeguard the hardier varieties—and offer some immunization against future bleaching events as global temperatures rise. “It's not a new idea, but they are the first to go through with it, and that's great,” says Charles Birkeland, a coral specialist at the University of Hawaii, Manoa. “Just limiting fishing isn't going to save our reefs. We need extra protection for the ones that are resisting bleaching, so they can serve as a brood stock for recovery.” Long before the nightmare of '98, Palau had built an impressive record in marine stewardship. The country boasts one of the highest proportions of territory set aside for MPAs in the world, with about a third of its near-shore waters—1300 square kilometers of reefs and lagoons—under varying fishing restrictions. Other Pacific nations are following Palau's lead: In the past decade, the number of MPAs grew from two to 189 in Fiji and from one to 20 in the Solomon Islands. “One village closes fishing in an area, the fish come back after a few years, and soon the next village wants one too,” says Michael Guilbeaux of the Community Conservation Network in Honolulu, Hawaii. Palau got off to a flying start thanks to a traditional culture that frowns on overfishing and a leader who champions MPAs. “The best way to protect our natural heritage is to use it as a source of income,” President Thomas Remengesau Jr. told Science. “Tourism is the sustainable thing for us.” Palau's prosperity—nearly all adults are employed—comes largely from its 50,000 tourist divers each year. Reefs vibrant with fish are a top priority. Last November, Remengesau sought to export that credo by challenging the rest of Micronesia to set aside 30% of near-shore waters for protection by 2020. Even for conservation-minded Palau, the massive 1998 bleaching event, which decimated reefs around the world, was a wake-up call. Three-quarters of barrier reef corals at Palau's Rock Islands lagoon, a popular diving site, perished. Ebiil, another barrier reef, was 98% destroyed. Inshore, many reefs fared better because they are accustomed to higher temperatures, whereas others survived because turbid waters and shade limited the sun's damage, says Rod Salm, a marine scientist in the Conservancy's Honolulu office who developed the bleach-resilience project. A critical insight led to a bold plan. Most reefs like Ebiil that have bounced back from bleaching are down current from reefs that suffered little, suggesting that coral larvae and fish from healthy reefs fueled the rapid recovery, Salm says. With that in mind, Noah Idechong (pronounced Idda- ONG), founder of the Palau Conservation Society, and others proposed weaving the nation's hodgepodge of MPAs into an ensemble, linked by currents, called the Protected Areas Network. “The key is to protect all the different reef types that survived bleaching or recovered exceptionally fast, because they will provide the larvae that will help damaged areas recover,” says Salm. “These reefs don't necessarily have the fish density that would make fishermen want to protect them.” The proposal resonated with Western donors. In 2005, The Nature Conservancy pledged$2 million, and Conservation International $1 million, to a trust, provided that Palau raises$9 million from other sources—which should not be a problem, says Eric Verheij, acting director of The Nature Conservancy's Palau office. The endowment's interest, along with a diver tax, should yield \$2.1 million a year for monitoring and antipoaching patrols. Idechong says he expects that the network, with one-third more area under protection than now, will be operational in 2 years.

Ebiil's rainbow reefs testify to the promise of that approach. Gliding past 2-meter strands of black coral, so prized by jewelers that it has been wiped out in many parts of the Pacific, Verheij zeroes in on what appears to be lifeless coral rubble. On closer inspection, the coral skeleton has been melded together by coralline algae and is studded with young polyps: a nursery of tiny phoenixes rising from the ashes of bleaching. Back on the boat, Verheij explains his philosophy. “Since you can't protect everything,” he says, “you try to protect the healthiest.” That philosophy seems to be paying off in Palau.

12. BIOMEDICINE

# Thymosins: Clinical Promise After a Decades-Long Search

1. Jean Marx

From an unorthodox experiment, two proteins have emerged that could prove useful in fighting infections and cancer and healing wounds

Thirty-three years ago, pediatric immunologists Arthur Ammann and Diane Wara of the University of California, San Francisco (UCSF), carried out a dramatic clinical experiment. Hoping to save the life of a 5-year-old girl named Heather whose immune system had failed, they gave her a mix of proteins called thymosin fraction 5 obtained from bovine thymus glands. The series of injections worked. Heather survived into her early 20s before succumbing to lymphoma.

This success at the dawn of the biotech age identified thymosins as a promising source of new therapies. Although other so-called biological response modifiers (BRMs), such as the immune-stimulating interferons, are now widely used in the clinic, for the most part, the thymosins have remained in the background. Now, some individual proteins isolated from thymosin fraction 5 may be poised to fulfill their early promise.

In late March, leading researchers in the thymosin field came together at George Washington University Medical Center in Washington, D.C., for a symposium entitled “Thymosins in Health and Disease.” Two came in for the greatest attention: thymosin α1, which is already approved for treating hepatitis B and C in several countries, although not in the United States, and is a potential cancer therapy; and thymosin β4, which might be useful for treating hard-to-heal wounds—including diabetic ulcers, bedsores, damaged corneas, and possibly even heart muscle injured by heart attacks. “It's really a wonderful molecule because it does so many things,” says ophthalmologist Gabriel Sosne of the Detroit Medical Center in Michigan, who has been studying thymosin β4's effects on corneal damage.

Immune booster The thymosins' origins trace back to work done more than 40 years ago by Allan Goldstein, then a postdoc at Albert Einstein College of Medicine in New York City. Goldstein's goal was to isolate the hormones assumed to underlie maturation of the immune system's T (for thymus-derived) cells, whose functions include helping the body defend itself against viral infections. In the course of that work, Goldstein produced thymosin fraction 5, which fostered immune cell function both in culture and in mice lacking thymus glands.

Subsequent work showed that fraction 5 contains at least 40 proteins. Goldstein's lab, now at George Washington University School of Medicine, has isolated several of them, including thymosin α1 in 1972 and thymosin β4 in 1981.

Strictly speaking, neither protein is a thymic hormone as originally conceived: Both are made in cells throughout the body as well as in the thymus. They are not related structurally, and both are small: Thymosin α1 consists of just 28 amino acids, and thymosin β4 contains 43. But their clinical potential could be big.

An early sign that thymosin α1 might have clinical value came in work by Enrico Garaci of the Istituto Superiore di Sanità and the University of Rome, “Tor Vegata,” and his colleagues. About 20 years ago, they found that thymosin α1 cooperates with other BRMs, including interferon and interleukins, to bolster the activity of immune cells known as natural killers, which are thought to help the body fight off cancer. Garaci proposed that combining thymosin α1 with chemotherapy drugs and interferon or interleukin might therefore produce more effective cancer therapies.

Studies in animal models seemed to bear that out. For example, when the researchers treated mice that had Lewis lung carcinoma with thymosin α1, interferon, and cyclophosphamide, they found that “this combination totally cures the tumors,” Garaci says. Before they disappeared, the tumors became packed with immune cells.

This good response may be due, he suggests, to another immune-boosting action of thymosin α1 that his team discovered a few years ago. The protein increases the expression of major histocompatibility proteins on tumor cell surfaces. These proteins display antigens for recognition by the immune system, thus “increasing the visibility of the target cells,” Garaci says.

In December of last year, SciClone Pharmaceuticals in San Mateo, California, and its European partner Sigma-Tau announced the results of a large phase II trial of treatment regimens that included thymosin α1 in advanced melanoma patients. The average survival time of 94 patients who got the standard melanoma therapy consisting of a dacarbazine drug (DTIC) and interferon α was 6.6 months, whereas that of 98 patients treated with DTIC plus thymosin α1 was 10.6 months. “The results were so promising that we are embarking on a phase III study,” said SciClone's Cynthia Tuthill at the meeting.

Thymosin α1's ability to bolster immune responses also caught the interest of virologists who treat hepatitis B and C. But even though the protein is widely used abroad, particularly in China, which has a big hepatitis B problem, the results of clinical trials conducted so far have been mixed. SciClone has found, for example, that adding the thymosin to pegylated interferon α in the treatment of hepatitis C patients produces no statistically significant improvement.

Still, small clinical trials have indicated that adding thymosin α1 to a drug regimen that includes the antiviral drug ribavirin as well as pegylated interferon α does lead to better responses than those produced by ribavirin and the interferon alone. SciClone and Sigma-Tau are now putting that to the test in a phase III trial that will include more than 500 patients. Results are expected in June 2008.

“I think [thymosin α1] may have a role as third drug [for hepatitis treatment] but not as a first or second,” says Vinod Rustgi, a specialist in liver diseases at Georgetown Medical Center in Washington, D.C. He also notes that the thymosin has been given to numerous people to date, and side effects have been virtually nonexistent.

## Mobility controller

Thymosin β4's mode of action is very different from that of thymosin α1, as a series of serendipitous discoveries in the early 1990s revealed. One of these came from Daniel Safer, then working with Vivianne Nachmias at the University of Pennsylvania School of Medicine in Philadelphia. While looking at how cells link together monomers of the protein actin to create polymeric filaments, which are important for cell migration, among other things, they found that thymosin β4 ties up the actin monomers until appropriate cell signals trigger filament formation.

At roughly the same time, Hynda Kleinman's team at the National Institute of Child Health and Human Development (NICHD) in Bethesda, Maryland, was looking for genes involved in new blood vessel formation, or angiogenesis. Among those the researchers found was none other than the gene encoding thymosin β4. Angiogenesis requires the migration of the endothelial cells that form blood-vessel linings, and when the NICHD group tested thymosin β4's effects on endothelial-cell migration, they were “astonished,” Kleinman says: A very small amount of the protein—1 nanogram—could promote the cell movements.

Even so, Kleinman recalls, journals weren't interested in publishing the discovery of yet another angiogenesis factor, so she decided to see whether thymosin β4 works in another model that requires cell movements, namely wound healing. It did, promoting healing by stimulating the migration of epidermal cell migration into experimental skin wounds on rodents and also stimulating collagen and blood-vessel formation. RegeneRx Pharmaceuticals in Bethesda, Maryland, a company founded by Goldstein, has begun clinical trials to test whether thymosin β4 can help treat chronic skin wounds such as bedsores and diabetic ulcers. (Kleinman, now retired from NICHD, is a member of the RegeneRx scientific and medical advisory board.)

Recent work also suggests that thymosin β4 therapy may help heal corneal damage, which Sosne, also a member of the RegeneRx advisory board, describes as “a big clinical problem.” Current treatments, he notes, can reduce the inflammation that often follows a corneal injury, but “there's nothing an ophthalmologist can do to promote” healing of the wound itself.

In work begun while a postdoc in Kleinman's lab, Sosne has shown that in animals, thymosin β4 both reduces inflammation and promotes the healing of alkali-induced wounds to the cornea. He has already treated one human patient on a compassionate basis, a diabetic woman who was blind in one eye and in danger of losing her sight in the other one after surgery. Fourteen days of treatment with drops containing thymosin β4 did bring about healing, although a minor injury caused the wound to reappear. At the end of March, RegeneRx announced that it was beginning a phase II trial to assess the safety and efficacy of thymosin eye drops in diabetic patients who had eye repair surgeries.

RegeneRx also plans a phase I trial aimed at assessing the safety of thymosin β4 injections as a possible therapy for heart attack victims. In late 2004, Ildiko Bock-Marquette, Deepak Srivastava, and their colleagues at the University of Texas Southwestern Medical Center in Dallas found that the protein is involved both in heart development and the maintenance of the adult heart. “Thymosin β4 appears to regulate the migration, survival, and perhaps even the beating frequency” of cardiac muscle cells, says Srivastava, who is now at UCSF and also a RegeneRx advisory board member.

In addition, the researchers found that the protein protects against the damage caused by heart attacks induced in mice by tying off their coronary arteries. Treated mice have less heart-muscle scarring and their hearts beat more strongly than those of controls. “All this happens with a single cardiac dose at the time of [arterial] ligation,” Srivastava says.

The idea that thymosin β4 can aid heart function got a further boost in January when Paul Riley of the UCL Institute of Child Health in London and colleagues reported the results of experiments in which they used RNA interference to block thymosin β4 production in the hearts of developing mouse embryos. In the absence of the thymosin, the researchers found disruptions in all aspects of the development of the coronary blood vessels and a consequent disruption of the development of the heart itself. The finding suggests that thymosin β4 might promote blood-vessel regrowth following a heart attack.

Still, there are concerns about administering thymosin β4 to human patients. Several investigators have evidence suggesting that it promotes the growth of cancerous tumors, possibly by enhancing new blood-vessel formation. Sosne says, however, that he never saw angiogenesis in the eyes of mice treated with thymosin β4 for 30 days. And Kleinman says she and her colleagues “saw no increase in spontaneous tumors and also none in the number of chemically induced tumors” in a transgenic strain of mice that overproduces the protein. Even so, patients who have ever received a cancer diagnosis will be barred from the clinical trials.

More than a quarter-century after that first medical experiment with thymosins at UCSF, the clinical prospects for at least two thymosin proteins are finally looking brighter.

13. SCIENCE IN ZIMBABWE

# Researchers Struggle to Adapt to Economic, Political Turmoil

1. Robert Koenig

With minimal government support, soaring prices, and a steady exodus of talent, Zimbabwe's scientists must be inventive to keep labs going

BULAWAYO, ZIMBABWE—Lecturers were on strike, computers were down, and labs were still dark when Peter Mundy parked his bike and unlocked his office at the National University of Science and Technology (NUST) here. Although the latest power outage threatened to defrost the owl, cobra, and other specimens in his lab freezer, the ornithologist was more concerned by the news that inflation had spiked to nearly 2000%—further eroding his salary and grants.

Those distractions would have frazzled most scientists around the world, but for Mundy they were all in a typical day's work. Like the African wildlife he studies, Mundy has adapted to survive in a harsh environment. “There's no internal research funding to speak of, and I have no budget for buying lab equipment,” says Mundy. “But we're trying to carry on.”

Down the hallway, ecotoxicologist Yogeshkumar Naik has taped a motto above his desk: “The impossible we do at once; miracles take a little longer.” These days, beleaguered researchers in Zimbabwe are in need of miracles. Their ranks are thinned by mass emigration, their budgets decimated by hyperinflation, and their international collaborations hurt by sanctions imposed against President Robert Mugabe's regime, which has unleashed police violence against its growing political opposition.

The contrasts are striking: Zimbabwe now has one of the world's lowest life expectancies, yet a massive investment in education during the 1980s and '90s gave the country Africa's highest literacy rate. Talented students and graduates are attractive to outside universities.

With many doctors and medical lecturers leaving the country, the University of Zimbabwe (UZ) in Harare recently asked one of the nation's best-known scientists—biochemist Christopher J. Chetsanga, a former member of UNESCO's executive board and until recently chair of Zimbabwe's National Council on Higher Education—to come out of retirement to teach biochemistry to medical students. “This country is in a terrible financial situation, but scientists have to find ways to carry on,” says Chetsanga, who is also president of the Zimbabwe Academy of Sciences. He told Science that many of those talented students tell him that “they plan to leave the country soon after they graduate.”

Conditions are “extremely difficult,” acknowledges biomathematician John Hargrove, who left Zimbabwe last year to head a South African Centre of Excellence that develops mathematical models to track the HIV/AIDS and tuberculosis epidemics in southern Africa. But Hargrove has maintained his Zimbabwe ties and research interests, helping arrange for a grant to NUST's applied math department to model epidemics in Zimbabwe. “We aim to become one of Africa's strongest groups in modeling infectious diseases,” says Winston Garira, whose NUST group has authored several recent papers in international journals.

Garira is one of a cadre of dedicated researchers who have opted, despite all the hardships, to stay put in Zimbabwe. Others at NUST include his colleague Mundy, who is trying to attract funding for a wildlife research unit; Naik, whose lab, with Swedish support, is investigating biomarkers for pesticide pollution; biochemist John S. Read, who is building an alternative-energy research group; and the dean of NUST's applied science faculty, Eddie Mwenje, who is studying gene flow between wild-type and genetically modified sorghum.

In what may be another sign that science is still hanging on, Zimbabwe founded an Academy of Sciences 2 years ago that has grown to 58 members and garnered international support. Its president, Chetsanga, says the academy helped convince the government last year to take steps to monitor bird flu and will sponsor a forum in June on the potential impact of global climate change in Africa. The academy is also trying to persuade the government to reconsider restrictive rules that ban planting genetically modified crops.

## Universal chancellor

The chancellor of all public Zimbabwean universities, by decree, is President Mugabe, whose photo hangs in administrative offices. When he first came to power in 1980, the University of Rhodesia (now UZ) was the lone public institution of higher learning; today, there are a dozen universities and three more planned. But that rapid growth, critics say, has come at the expense of academic and research quality.

Although UZ remains influential, one of the most ambitious new universities is Bulawayo's NUST, which opened a dozen years ago and now has about 5000 students. At first glance, the campus seems to be growing, with attractive buildings and an imposing row of unfinished structures bristling with construction cranes. But there are no workmen in the empty shells. Construction has been virtually frozen for years, prompting one scientist to describe the campus as “a parking lot for unused cranes.”

“We still hope to finish these buildings,” says the optimistic vice chancellor, veterinary scientist Lindela R. Ndlovu. His deputy, organic chemist Samson Sibanda, is confident that the university can thrive despite its budget crunch by reaching out to Zimbabwe's “science diaspora,” especially in neighboring countries such as South Africa, to “create research partnerships.” NUST's aim is to tap foreign sources to help equip the rows of laboratories that stand empty, devoid of instruments or even reagents. “We've got the labs, but we need the hardware,” says Mundy. The strategy has worked in a few cases: Naik was able to equip his NUST lab with hard-currency grants from Sweden's International Foundation for Science.

Last fall, the university hired Moses J. Chimbari, a former Fulbright student in public health at Johns Hopkins University in Baltimore, Maryland, to help other researchers land foreign grants. Chimbari is systematizing the process and educating the university staff. One of the biggest problems, he says, is “the great disparity between the government's official exchange rate and the unofficial rate.” A large share of many grants goes to government currency traders.

Some foreign donors and their Zimbabwean grantees have been able to get around the official requirements, which at one point exchanged dollars at 80 times less than market value, by purchasing lab equipment and reagents through foreign accounts and then shipping them into Zimbabwe. But even if donors beat the exchange problem, inflation takes a toll. Says Hargrove: “When you give grants to Zim scientists, it's extremely difficult to get that money to the researchers without it being diluted.”

Inflation's impact is insidious. Over the last couple of years, the Education Ministry has been in a constant battle over the wages it sets. University lecturers have gone on strike several times because their meager salaries have not kept up with inflation, which the International Monetary Fund predicts could reach 5000% by year's end. “I'm barely able to pay the rent and feed my family,” lamented lecturer Donald Mlambo, who says prices increase so rapidly that “we would need a weekly salary adjustment to keep up.” Students, unable to pay modest tuition costs, are angry, too. Last year, rioters at Bindura University of Science Education in northern Zimbabwe burned down a computer science laboratory.

“Hyperinflation affects everything,” says medical researcher David Katzenstein of Stanford University in Palo Alto, California, who has worked with colleagues in Zimbabwe over 2 decades. “The economics are crazy, but the researchers have admirable talent and dedication.”

Although Mugabe harshly criticizes Western “imperialists,” the government does not turn away help from an array of foreign sources, including the U.S. National Institutes of Health (NIH) in Bethesda, Maryland, and the Centers for Disease Control and Prevention in Atlanta, Georgia. “In medical research, most of the resources are coming from North America and Europe,” says Katzenstein, who is working on a project with Peter Mason of the Biomedical and Research Training Institute in Harare to provide laboratory, clinical, and epidemiological training to Zimbabwean researchers.

That initiative, directed at the HIV/AIDS and tuberculosis epidemics, is funded by NIH's Fogarty International Center. Another NIH grant helps fund a collaborative research program between UZ and the University of California, San Francisco, on ways to reduce the vulnerability of women to HIV and other sexually transmitted diseases. Yet another NIH-funded program, which involves the University of Buffalo's School of Pharmacy, helps Zimbabwe monitor drugs to treat HIV and tuberculosis infections. The main partner in Harare is UZ pharmacologist Chiedza Maponga, who helped plan the 2002 rollout of Zimbabwe's free antiretroviral therapy program; with support from foreign donors, it now reaches an estimated 10% of the infected population.

“We need more bridge-building programs like this,” says Maponga. His UZ department has devised ways to monitor the quality of generic antiretroviral drugs and conduct clinical studies of drug interactions with African herbal medicines that are sometimes used to treat HIV/AIDS. He is also developing a monitoring system “to help show international donors that their money is being put to good use.” In particular, it is important to reassure American and European biomedical assistance programs that sanctions aimed mainly against Mugabe and high-ranking members of his government are being observed.

The exodus of Zimbabwean physicians is another factor limiting the country's participation in research. The number of doctors remaining may have dropped, some observers say, to less than half the official level of about 2000. Rampant emigration and AIDS deaths have had a substantial impact; some demographers and epidemiologists suspect that the nation's population may have fallen more than 20% below the official level of 13 million.

Yet there is no dearth of young people who want to study science, researchers say. Even if the equipment is missing and labs are sometimes dark, the students are bright. The real challenge will be to persuade the best of them not to depart for greener pastures as soon as they get an opportunity. Says biochemist Read, who returned to teach in Zimbabwe after years of study abroad: “Our greatest assets are the bright young Zimbabweans we are privileged to teach and do research with.”

14. EVOLUTIONARY ECOLOGY

# Variable Evolution

1. Elizabeth Pennisi

Researchers are discovering the intricacies of relationships in which one organism sometimes influences the evolution of another and sometimes doesn't

Coevolution is a tale of intimacy. Two species—a parasite and its host; a pollinator and its plant—evolve in lockstep, adapting ways to deal with willing, and sometimes unwilling, partners. But occasionally, evolution gets off track.

In north-central Nevada, for example, the Clark's nutcracker has a cozy relationship with certain pine trees: The birds carry off seeds and cache some of them for future use, helping new seedlings get started. For its part, the pine tree has made extracting seeds child's play by evolving short cones bursting with seeds that are covered by thin, easy-toremove scales. But in the Rocky Mountains, a ménage à trois has developed, in which the pine trees are torn between defending their seeds against squirrels and helping out the nutcracker. As a result, the birds must make do with long, heavy cones with thick scales and relatively few seeds. Coevolution has practically stalled out.

When biologists first started thinking about coevolution some 40 years ago, they didn't appreciate this complexity. Over the years, they have marveled at bird bills exquisitely shaped for feeding efficiently on products of specific plants, and they've learned about arms races in which snakes, insects, and other predators develop ways to outwit the ever-better defenses of their prey. But there have been nagging inconsistencies in many of these observations: Some species pairs don't have the same adaptations everywhere.

Ecologists have found that, in organisms from birds to bacteria, coevolution is not a sure thing. “The interactions between pairs of species have different intensities in different ecological settings,” says May Berenbaum, an entomologist at the University of Illinois, Urbana-Champaign. A decade ago, evolutionary ecologist John Thompson of the University of California, Santa Cruz, came up with a theory to explain these geographical variations in coevolution and coined the term “geographic mosaics.” And in the past few years, because of its relevance to understanding evolution, biodiversity, and species invasion, there has been “a surge in interest” in the theory, says Richard Gomulkiewicz, an evolutionary biologist at Washington State University in Pullman.

## Coevolution's mosaics

Thompson proposed that the survival advantage provided by coevolution was inconsistent because environmental conditions, and hence the forces of natural selection, differ from place to place. In retrospect, this idea seems self-evident, but at the time “people generalized [what they found] from one location and extrapolated to everywhere else for that species,” says Craig Benkman, an evolutionary ecologist at the University of Wyoming in Laramie.

If researchers looked more broadly at different populations of interacting species, Thompson predicted, they should discover “hot spots”—with intense interactions between partner species and rapid coevolutionary change—and “cold spots”—areas where the two species have little influence on each other's evolutionary trajectories. Environmental factors, including the presence of other species, should affect hot-spot distribution by making coevolution more or less advantageous to the partners. The mobility of the partners should matter as well: Gene flow from one set of coevolving populations to another should speed or impede the evolution of specializations.

Thompson's fellow ecologists were skeptical at first. “Many of us were left wondering how to address such a complex set of processes and were frustrated with the lack of very specific, testable predictions,” says Edmund Brodie III, an evolutionary biologist at the University of Virginia, Charlottesville. Recalls Thompson, “The criticism I got was 'Show me the data.'”

Today, however, the theory is much more palatable. In 2005, Thompson published a book, The Geographic Mosaic of Coevolution. He and other theoretical biologists have come up with more detailed models to predict how species might change over space and time, helping field researchers focus their studies. In 2006, the number of publications was expected to be double that of 6 years ago. “We're suddenly seeing the data for a whole variety of interactions,” Thompson says.

## Third-party interference

Even as Thompson was first formulating his geographic-mosaic theory, Benkman was coming to similar conclusions based on his long-term studies of crossbills and other birds that feed on pine seeds. In the 1990s, his work suggested that the presence of squirrels in certain pine forests of the Rocky Mountains influences cone shape and scale size. Now he and Adam Siepielski have extended that work with a careful look at the ecological and evolutionary crosstalk between squirrels, Clark's nutcrackers, and pine trees in western North America. They find the geographic mosaic and the cold and hot spots Thompson envisioned.

The squirrels and birds both eat seeds, but only the nutcrackers help the tree by dispersing some seeds: A single bird can carry off up to 98,000 seeds a season, sometimes as far as 22 kilometers. When squirrels harvest cones, few seeds ever germinate. In 2004 and 2005, Siepielski and Benkman looked at limber pine or whitebark pine forests with or without squirrels and assessed cone and seed characteristics as well as bird and squirrel consumption of seeds.

The results were similar irrespective of the pine species. Nutcrackers preferred cones with thinner scales and more seeds, characteristics of the squirrel-free stands. But forests with squirrels had wider, heavier cones with thicker scales and fewer seeds that were harder for the birds to retrieve, Siepielski and Benkman report in the May issue of Ecological Monographs. Thus, squirrel-infested forests represented cold spots. “The presence or absence of the squirrel drives the interaction between the pines and the nutcrackers,” says Benkman.

Sometimes three-way interactions can lead to new species, Benkman and Julie Smith of Pacific Lutheran University in Tacoma, Washington, reported in the April issue of American Naturalist. The newcomer, the South Hills crossbill, lives in pockets of Idaho forest where squirrels are absent. There, unusually thick scales have resulted in bigger bills, which in turn eventually led to changes in birds' calls. With that change, the birds'attractiveness to crossbills from elsewhere diminished. “The selection is so different with and without squirrels, it's causing one population to speciate from the others,” says Benkman.

## Arms races

Berenbaum has also found that a third species can throw a wrench in the works of coevolution. Over the past 15 years, she and entomologist Arthur Zangerl, also from the University of Illinois, had found a tight correspondence between the types of toxins produced by wild parsnip and the detoxifying capabilities of parsnip webworms found in the United States. Both plant and caterpillar are native to Europe, with the parsnip arriving in North America about 400 years ago, followed by the webworm about 250 years later.

What's striking, notes Berenbaum, is how quickly the webworm and the parsnip established a tight correspondence once the two met up in North America. Zangerl has analyzed the toxin profiles of herbarium specimens of wild parsnips from collections that date from 1836 to the present. His 2005 analysis shows that within 20 years of the webworm's arrival, the toxin content increased. And, judging from the U.S.-based webworm's current ability to chow down on parsnip with impunity, the webworm has rapidly improved its ability to break down parsnip toxins. “That's something we don't see happening in the European samples,” Zangerl notes. The reason is the presence of a third player in Europe: Webworms there often munch on hogweed, a less toxic plant that's not present in North America, Berenbaum and Zangerl reported in the December 2006 issue of Ecology.

At the University of Virginia, Brodie is examining another coevolutionary tale, that between toxic newts and their snake predators. He and his colleagues have found hot spots—where garter snakes are rapidly evolving resistance to ill effects from snacking on newts—and cold spots, where resistance to the newt poisons has not evolved. They are now looking to see whether other predatory snakes have the same hot and cold spots. “If so, it is pretty strong evidence that there are major geographic or biogeographic patterns that influence the mosaic and not simply some stochastic process,” Brodie says.

Brodie hopes to investigate how gene flow affects these geographic mosaics. When resistant snakes move into an area populated by vulnerable individuals, for example, they should have the advantage and “warm up” a cold spot. Brodie knows that mutations in a gene for a sodium channel in muscle confer resistance to the newt poisons, and he and his colleagues are sequencing this gene with the hope of using single-base differences between individuals as a way to monitor gene flow throughout the mosaic.

To date, though, the most solid evidence that gene flow plays a major role in geographic mosaics comes from an experiment in which Thompson and his colleagues monitored how quickly bacteria evolved resistance to bacterial viruses (which in turn develop ways to evade this resistance). In 2004, he, Samantha Forde in his lab, and Brendan Bohannan of the University of Oregon, Eugene, first showed that the intensity of this arms race depended on how nutrient-rich the environment was, with resistant bacteria evolving faster in richer media. But when the researchers put bacteria from rich media in with bacteria with suboptimal nutrients, the evolution of resistance sped up in those communities, thereby changing the coevolutionary dynamics.

Working out how geographic mosaics arise, and why, has important ramifications. Agencies charged with protecting borders against invasive species are struggling to predict the worst offenders. “The geographic-mosaic theory can be a tool for improving predictions,” says Berenbaum. And Benkman thinks the data to date on the effects of a third-party species suggest caution to wildlife biologists thinking about reintroducing species, particularly mammals, into areas where they have not lived for centuries. Finally, conservation policies need to consider how species might differ genetically across space, and how the coevolutionary paths they travel might vary. “If in conserving biodiversity we aim to represent the full array of the species, then we need to cover a broad sweep of these areas,” says Jeremy Burdon, an evolutionary biologist at the Commonwealth Scientific and Industrial Research Organisation Division of Plant Industry in Canberra, Australia.

For these reasons and others, testing the geographic-mosaic theory has increasing appeal. “People are motivated to see if these different processes are present and if they are important,” notes Gomulkiewicz. And Paul Rainey, an evolutionary geneticist at the University of Auckland, New Zealand, agrees: “There is a huge opportunity here for research.”