# News this Week

Science  26 Mar 2010:
Vol. 327, Issue 5973, pp. 1562
1. Research Funding

# Health Bill Backs Evidence-Based Medicine, New Drug Studies

1. Jocelyn Kaiser

Buried within the 2400 pages of the landmark health care reform bill passed by the House of Representatives this week and signed by President Barack Obama are several provisions that touch on clinical research. Two are aimed at determining which therapies work best and identifying researchers' financial conflicts. A third, which has flown under the radar until now, would fund a new push in drug development at the National Institutes of Health.

Most directly tied to health care is a provision that focuses on comparative effectiveness research (CER)—evidence-based studies that compare the value of medical treatments, such as two different drugs, or a specific drug versus surgery. Proponents hope that these studies will improve the quality and lower the cost of health care by identifying the best treatments. The bill creates an independent, nonprofit Patient-Centered Outcomes Research Institute to conduct this research. It picks up on the $1 billion in 2-year funds for CER that last year's stimulus package gave to the National Institutes of Health (NIH) and the Agency for Healthcare Research and Quality (AHRQ) (Science, 27 November 2009, p. 1183). Some lawmakers wanted to put the new institute within AHRQ, a unit of the Department of Health and Human Services (HHS), which has been the federal home for CER. Creating a new organization, they argued, would be duplicative and wasteful. Others felt independence would encourage involvement from “stakeholders” such as doctors and patients. “Some feel it's good to get a fresh take outside existing structures,” says Steven Pearson, president of the Institute for Clinical and Economic Review at Harvard Medical School in Boston. The new institute will set a research agenda and award contracts mainly through NIH and AHRQ. Funding for the institute will rise to$150 million in 2012, to be supplemented after that by a trust fund drawn from fees on health insurance.

A less-noticed section of the health legislation creates a new translational research program within the NIH director's office aimed at drug development. Called the Cures Acceleration Network (CAN), it is the brainchild of Senator Arlen Specter (D–PA). CAN will give out grants and contracts of up to $15 million a year to companies, academic researchers, and patient groups to help bridge the “valley of death”: the gap between the initial discovery of a drug and the lab and animal studies a developer needs to conduct to obtain regulatory approval for clinical trials. The NIH director will decide who gets the competitive awards, which must go for “high need cures” or high-priority therapies that are unlikely to be developed by the commercial market. CAN will also have an advisory board, at least one-third of whose 24 members will be from patient advocacy groups. Amy Comstock Rick, executive director of the Parkinson's Action Network in Washington, D.C., which pushed for CAN, says her group's disease illustrates the problem: Companies haven't been interested in Parkinson's because the market isn't that big and a lack of biomarkers makes it hard to tell if treatments are working. “We believe it's time for the NIH to expand its piece of the pipeline a little bit,” Rick says. It's not clear yet who will pay for CAN. Although the bill authorizes up to$500 million a year, nothing has been appropriated. Some biomedical research groups worry that money would be shifted from existing NIH programs to fund CAN. “We are concerned in a time of limited resources that it could constrain research budgets,” says Carrie Wolinetz, spokesperson for the Federation of American Societies for Experimental Biology in Rockville, Maryland, which did not take a position on CAN. The bill also elevates NIH's Center on Minority Health and Health Disparities to an institute.

Finally, the bill puts into place a widely supported proposal to shed light on the payments that drug and medical-device companies make to physicians and hospitals. Starting in 2013, the so-called Physician Payments Sunshine Act provisions require that such companies file annual reports to HHS listing all payments or other “transfers of value” to doctors and hospitals of more than $10 per event or$100 total per year. The information will be posted in a public online database. The legislation is a response to a Senate investigation that found such payments are often not disclosed and may be influencing prescribing decisions and biasing the results of clinical studies.

An earlier House version of the provisions would have covered all biomedical scientists, including those without a medical degree. But supporters say the language in the final bill is an important start and could be expanded later. It “will better protect patients and will help restore trust in our health-care system,” says Allan Coukell, director of the Pew Prescription Project, a proponent of strong disclosure rules.

2. Swine Flu Pandemic

# What's Old Is New: 1918 Virus Matches 2009 H1N1 Strain

1. Jon Cohen

The “novel” H1N1 swine influenza virus that last year caused the first human pandemic in 4 decades has one feature that is hardly novel: Its surface protein, hemagglutinin (HA)—which spikes cells and starts an infection—closely matches the HA in the H1N1 virus responsible for the 1918 pandemic. Separated by 91 years, the two strains of the highly mutable virus ought to be vastly different. This newfound similarity answers many mysteries about the 2009 pandemic, including why it largely spared the elderly. The new findings from different research groups also suggest intriguing explanations for how the 1918 influenza virus has evolved since it swept across the globe in several waves, killing more than 50 million people by the winter of 1919. And the investigators are proposing provocative—some say far-fetched—vaccination strategies to preempt future pandemics.

Influenza researchers not involved with the new studies say they pull together several concepts about the relationship between influenza, the immune system, and different species that have been gaining ground. “I really find this a fascinating story,” says Rino Rappuoli, head of vaccine research at Novartis Vaccines & Diagnostics in Siena, Italy. “It's the lesson of evolution.”

One study published 24 March in Science Translational Medicine shows that even though nearly a century separates the widespread circulation of the two viruses in humans, mice given a vaccine against the 1918 strain produced antibodies that “neutralized” the novel 2009 strain. When the team flipped the experiment and used a 2009 pandemic vaccine in mice, the immune response stopped the 1918 virus. “We kind of did a double take,” says virologist Gary Nabel, head of the Vaccine Research Center at the U.S. National Institute of Allergy and Infectious Diseases (NIAID) in Bethesda, Maryland, and the lead researcher on the project. “It was an unexpected finding, but it all makes sense when you look at the data collectively.” Although he acknowledges the limits of extrapolating from mouse to human immune systems, Nabel says in this restricted analysis of antibodies in response to proteins, “it's a very reasonable model.”

Influenza and the human body are like opposing Cold War spies, with the virus repeatedly donning new disguises and the human immune system racing to foil each incarnation. HA is the virus's main quick-change artist. Antibodies produced by the immune system, in turn, try to neutralize HAs by binding to them, blocking the virus from entering cells. As a rule, influenza viruses change so quickly that a vaccine against a regular “seasonal” strain circulating one year may have little impact against a similar strain a few years later. Yet the HA proteins on the 1918 and 2009 pandemic viruses look remarkably similar in close analyses done in both Nabel's study and a separate one published online this week by Science that includes x-ray crystallographic data (www.sciencemag.org/cgi/content/abstract/science.1186430). These two reports also clarify the evolution of seasonal strains in the decades between the two pandemics.

The two studies focus on the top part, or the head, of the HA, which is the business end of the protein when it comes to the infection process. Each research group calculated that the amino acids in the head of the two pandemic HAs were only about 80% similar, which is roughly the divergence seen between two seasonal strains. This would suggest that antibodies against the 1918 and 2009 pandemic strains would not cross-neutralize. How then to explain the mouse results?

Influenza foils antibodies by changing HA's amino acids—a process called genetic drift. Genetic drift occurs in two ways. One is direct: An amino acid change can alter the structure of the protein so that the “arms” of the antibodies can't get a good grip. The second mechanism involves sugars. Specific chains of three amino acids create “glycosylation sites” that allow sugars made by the cell to attach to the viral protein. These sugars form clouds around the HA, masking the ability of antibodies to “see” the right amino acids. When Nabel, Terrence Tumpey of the U.S. Centers for Disease Control and Prevention (CDC) in Atlanta, and their co-workers focused on the amino acids in a discrete region of the HA tip that plays a critical role in binding to cells, they discovered a 95% similarity between the old and new pandemic strains. Comparisons between seasonal and the pandemic strains in this region found less than 70% similarity.

In the second study, a team led by structural biologist Ian Wilson of the Scripps Research Institute in San Diego, California, went further, linking the amino acid sequence analysis to the three-dimensional structure. Wilson's group crystallized the 1918 and 2009 pandemic viruses and showed that the HA heads had distinctly similar shapes. What's more, the few amino acid differences between the strains were mainly confined to one small region of the head. In an additional experiment, they took an antibody from survivors of the 1918 epidemic, crystallized it in a complex with the 1918 virus, determined the amino acids in HA used to bind the antibody, and then showed that the 2009 pandemic strain had the same amino acids. “The closest related structure that we have to the current 2009 swine flu is the 1918 structure,” says Wilson, who also analyzed sequences from many other influenza viruses that have circulated in humans between those two pandemics. “The papers come to similar conclusions about why some people are more resistant to the current swine flu.”

Both the Wilson and the Nabel studies show that the HAs of the two pandemic strains also look markedly different from seasonal viruses when it comes to sugars. All seasonal strains have at least two glycosylation sites on the top of their HAs, whereas both the pandemic strains are bald. “The absence of glycosylation at the top of these molecules is making a huge difference in the immune response,” says CDC virologist Ruben Donis, who was not involved with the study.

The new studies are helping to clarify how influenza viruses have used sugars in their evolution since 1918, says NIAID virologist Jeffrey Taubenberger, a leading investigator of that devastating pandemic. “All the influenza viruses in humans are descendants of the 1918 virus,” says Taubenberger, who published mouse experiments 8 March online in Influenza and Other Respiratory Viruses that similarly show how the 1918 virus protects against the 2009 pandemic strain. “Over the last 91 years, we've been in one large 1918 pandemic era.”

By analyzing the difference in the earliest available seasonal HAs from 1933 to 2009, Nabel's group found that some amino acid drift occurred and changed the structure of the HA head, but after that the bald virus started accumulating new glycosylation sites. Nabel posits that the bald 1918 virus could tolerate only a limited number of amino acid changes that altered its structure. “At a certain point, there's a fitness cost for adopting a new mutation, so the virus says, ‘What else can I do?’” says Nabel.

In a perspective he co-authored in Science Translational Medicine about the study, Novartis's Rappuoli says people exposed to the bald 1918 virus and its sugar-free descendants that subsequently circulated for a few decades developed an immunity that later protected them from the 2009 pandemic strain. “Evolution does not necessarily bring new things,” says Rappuoli. “It sometimes brings things back.”

The new evolutionary insights are leading researchers to revisit assumptions about another immune-evading trick that influenza exploits called genetic shift. Influenza viruses can swap whole genes, or reassort, with different strains. There are 16 different HAs and nine different neuraminidases, which is what the H and N numbers designate. The 1957 pandemic strain was just such a reassortant, with the H1N1 becoming an H2N2. A pandemic in 1968 saw a switch to H3N2. So many researchers assumed that the next pandemic would occur with H5, H9, or some other HA that few human immune systems had seen. “No one in the flu community predicted it would be an H1,” says Taubenberger. “It took everyone by surprise, including me.” Basically, immunity against the 1918 H1N1 had waned enough to create a niche for another bald H1 to return.

As Rappuoli notes, one of the lessons from the 2009 swine flu pandemic is that the reason the H1 remained bald in pigs since 1918 is because viral evolution differs dramatically in humans and other species. Humans live many decades, creating long-term relationships between the immune system in individuals and the influenza viruses they encounter during their lifetimes. “The virus is pushed to evolve quickly in humans if it wants to survive,” says Rappuoli. Not so in pigs and birds, which are short-lived species—especially those on farms—that can pass influenza viruses to humans. The H1 in pigs thus has had little pressure to mutate and has remained frozen in evolution, says Donis, who calls swine “a warm freezer.”

Rappuoli thinks a clearer understanding of the relationship between influenza viruses in humans and other species could be used to craft a new vaccination strategy to prevent pandemics. He proposes making vaccines against viruses that caused earlier pandemics by pulling out “archived” strains that have remained frozen for decades in pigs and birds. Chicken farmers might similarly be given an H5N1 vaccine to reduce the chances of that highly virulent “bird flu” strain, which does not spread well between people, adapting to humans.

Nabel offers his own forward-looking vaccine strategy. He predicts that the 2009 pandemic strain will follow the mutational path of the 1918 pandemic virus; as his paper went to press, he says he detected that process in four isolates. A vaccine could be developed that artificially glycosylates the novel 2009 H1N1 in a way that mimics glycosylated descendants of the 1918 strain. “We can look at how 1918 evolved in response to humans and preemptively take steps to contain and maybe even drive the 2009 pandemic strain out of existence,” says Nabel.

Taubenberger notes that huge practical hurdles stand in the way of such “boutique” vaccines. But he, too, thinks the 2009 pandemic H1N1 may help humans outwit influenza in the long run. In particular, he says the 2009 pandemic virus might outcompete the H3N2 seasonal strain that now causes most of the deaths in the elderly. “It would be fantastic if a new pandemic virus, in which the elderly are somewhat protected, replaced a nasty seasonal virus that causes serious morbidity and mortality.” Now, that would be a novel twist to the 2009 swine flu pandemic.

3. Science and Religion

# Latest Prize Bolsters Templeton's Shift to Mainstream

1. Yudhijit Bhattacharjee

In 2005, molecular biologist Matthew Gibson wondered whether to accept a grant he had received from the John Templeton Foundation to study how the apparently random process of cell division leads to a predictable honeycombed pattern in the epithelium of many organisms. Gibson, then a postdoc at Harvard Medical School in Boston, knew that the foundation was interested in how order emerges from randomness, a pet theme for proponents of intelligent design (ID). If he took the grant, Gibson wondered, would he be playing into a religious agenda?

Gibson was not the only scientist to harbor such doubts about the foundation, which seeks to promote a dialogue between science and religion. In the past, Templeton has supported conferences and projects linked to the Discovery Institute, an ID think tank. But it subsequently disavowed support for the ID movement, allaying the fears of many critics. This week, the foundation took another step in that direction by awarding its annual $1.5 million Templeton Prize to Francisco Ayala, a priest-turned-biologist who for decades has campaigned against the teaching of creationism and ID in the science classroom. The 76-year-old Ayala, a professor at the University of California, Irvine, has sought to foster mutual respect between science and religion through lectures and writings on topics such as morality. “If they are properly understood, they cannot be in contradiction because science and religion concern different matters,” says Ayala, a former president of AAAS (publisher of Science). He says the conflict has grown less intense since Templeton funds helped to launch a program in the mid-1990s called Dialogue on Science, Ethics, and Religion at AAAS, which continues to be supported by the foundation. Some scientists objected at the time, he recalls. “They said, ‘What business does science have talking to religion?’ I don't think there are many thoughtful scientists who would make that point today.” However, some remain staunchly opposed to Templeton's mission. “They are using the prestige and authority of science to improve the prestige and credibility of theology,” says Daniel Dennett, a philosopher at Tufts University in Medford, Massachusetts. In his opinion, Templeton-funded discussions between scientists and religious figures do for religion what debates between ID proponents and evolutionary biologists would do for ID: “They create the perception that scientists and theologians are academic co-equals, which they are not.” One program that Dennett worried has a religious slant is the Science of Generosity initiative at the University of Notre Dame in Indiana, begun last year with$5 million from the foundation. The program has awarded a handful of research grants, including $250,000 to study how empathy affects charitable donation and$400,000 to explore how generosity spreads through social networks. “What they are trying to do is to paint certain topics with a holy glow,” says Dennett.

Not so, says the program's director, Notre Dame sociologist Christian Smith. He says the initiative in no way presumes that generosity “is somehow God-given.” The choice of the term “generosity,” he explains, was to create an umbrella theme for different but related topics such as altruism and voluntary blood donation. “Most projects that we're going to fund will be about operations of the mind, social psychology, and related concepts,” he says. Joseph Henrich, an anthropologist at the University of British Columbia in Vancouver, does not see a religious taint. “There may be a little bit of marketing” in how the program has been framed, he says, “but it's perfectly legitimate.”

Even those who are put off by Templeton's mission agree that the foundation does not attempt to influence the outcomes of the research and discussions it sponsors. “I am not enthusiastic about the message they seem to be selling to the public—that science and religion are not incompatible; I think there is real tension between the two,” says Steven Weinberg, a Nobel Prize–winning physicist at the University of Texas, Austin, who has been an outspoken critic of religion. “But for an organization with a message, they are pretty good at not being intrusive in the activities they fund. I don't wish them well, but I don't think they are particularly insidious or dangerous.”

The foundation has also recognized the pitfalls of associating with the ID community after being criticized by scientists for giving a grant in 1999 to ID proponent William Dembski, a fellow at the Discovery Institute, and later to Guillermo Gonzales, an astronomer at Iowa State University who used the funds to research a book arguing in favor of ID. In a 2007 letter to the Los Angeles Times, Templeton's former vice president for communications explained that “[i]n the past, we have given grants to scientists who have gone on to identify themselves as members of the intelligent-design community. We understand that this could be misconstrued by some to suggest that we implicitly support the movement, but this was not our intention at the time, nor is it today.”

Barbara Forrest, a philosopher at Southeastern Louisiana University in Hammond, says that “Templeton realized that the relationship was a liability to their mission.”

Gibson says he decided to accept the foundation's money “after poking around and finding nothing fishy.” Now a researcher at the Stowers Institute for Medical Research in Kansas City, Missouri, Gibson admits that he may have been influenced by need. “At the time, I don't think anybody else would have funded what we were doing.” But he's pleased with how things turned out, including a paper in Nature. “The fact that the [foundation] appreciated a philosophical element of the research—which I was neutral about—is fine with me,” he says.

4. ScienceNOW.org

# From Science's Online Daily News Site

The Best Refrigerator Magnet Ever? There are limits to just how magnetic a material can be, or so researchers thought. A compound of iron and nitrogen is about 18% more magnetic than the most magnetic material currently known, a team of materials scientists claims. If such magnets could be produced commercially, they could, for example, allow electronics manufacturers to equip computer hard drives with smaller “write heads” capable of being crammed with more information.

Mosquitoes Become Flying Vaccinators A group of Japanese researchers has developed a mosquito that spreads vaccine instead of disease. Even the researchers admit, however, that regulatory and ethical problems will prevent the critters from ever taking wing—at least for the delivery of human vaccines.

Landlubber Caterpillars Take to the Water Adolescence is a tough time for anyone, but what if, on top of your growing pains, you had to learn how to breathe underwater? Hawaiian caterpillars take it all in stride. Researchers have discovered 12 species of Hawaiian moths whose caterpillars are equally comfortable submerged in a stream or beached on a bone-dry strip of land. The feat makes them unique among insects, and maybe even among animals, the researchers say.

Nano-Gadget Holds the Salt Water desalination plants can effectively turn seawater into drinking water, but they're hardly portable. Now a team has created a salt-removing gadget so small that hundreds of them could fit onto a penny. If researchers can scale up this invention into a working device, it could generate up to a glass of fresh water per minute using about the same amount of energy as a table lamp does.

5. Human Evolution

# Ancient DNA From Siberia Fingers a Possible New Human Lineage

1. Michael Balter

When ancient-DNA expert Svante Pääbo gave his colleague Johannes Krause a sample of a 40,000-year-old human finger bone from a Siberian cave, he had only one question: Was its mitochondrial DNA (mtDNA) that of a Neandertal or a modern human?

It was neither. Evolutionary geneticists Pääbo and Krause, of the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, have apparently identified a new lineage of ancient human, the first time that this has been done using ancient DNA and not fossil bones.

“I couldn't believe it,” Pääbo says. “I thought Johannes was pulling my leg.” The complete sequence of mtDNA from the finger bone, reported online this week in Nature, suggests that Central Asia was occupied at that time not only by Neandertals and Homo sapiens but also by a third, previously unknown hominin lineage. “This is the most exciting discovery to come from the ancient DNA field so far,” says Chris Tyler-Smith, a geneticist at the Sanger Institute in Hinxton, United Kingdom. “A stunning piece of work,” says Terence Brown of the University of Manchester in the U.K.

The work complicates the human story, much as the discovery of the controversial H. floresiensis—a.k.a. the hobbit—has upset earlier and simpler views of early human migrations around the globe. If four hominins including the hobbit were alive about 40,000 years ago, “the amount of [human] biodiversity … was pretty remarkable,” says geneticist Sarah Tishkoff of the University of Pennsylvania. For now, Pääbo's team is not naming the new lineage.

The finger bone—a phalanx whose species could not be identified—was found in 2008 at Denisova Cave in Russia's Altai Mountains, where archaeologists led by co-authors Michael Shunkov and Anatoli Derevianko of the Russian Academy of Sciences in Novosibirsk have worked for decades. The cave, which has many archaeological layers spanning about 100,000 years, has yielded both Neandertal and modern human stone tools, personal ornaments, and a small collection of hominin bones too fragmentary to be identified. The bone came from a layer radiocarbon-dated to between 48,000 and 30,000 years ago. The team ground up a 30-milligram sample and extracted and sequenced all of the 16,569 base pairs of its mtDNA genome, using new techniques Pääbo's group has successfully employed to sequence both Neandertal and prehistoric modern human DNA (Science, 17 July 2009, p. 252). The team compared the new mtDNA sequence with that of 54 living people from around the world, a roughly 30,000-year-old modern human from another Russian site, and six Neandertals.

They got a big surprise: Although Neandertals differ from modern humans at an average of 202 nucleotide positions in the mitochondrial genome, the Denisova hominin differed from modern humans at an average of 385 positions and from Neandertals at 376 positions. When mtDNA from chimpanzees and bonobos was added to the mix, the researchers were able to estimate that the new hominin's mtDNA had shared a common ancestor with Neandertals and modern humans about 1 million years ago.

The team appears to have avoided contamination and other problems that have plagued ancient DNA research, says Maria-Eva Geigl of the Jacques Monod Institute in Paris, calling it a “great paper … technically well done.”

But who was this mystery hominin? The team says the date is too late for Asian H. erectus, which first migrated out of Africa into what is now the republic of Georgia and Java about 1.8 million years ago. And it's too early for H. heidelbergensis, which came on the scene in Africa and Europe about 650,000 years ago and is thought by many to be the common ancestor of modern humans and Neandertals. There's “no evidence” that these or other known species “persisted that late” in mainland Asia, says paleoanthropologist Russell Ciochon of the University of Iowa in Iowa City, although he thinks a claimed 27,000-year-old date for H. erectus on the island of Java remains possible.

Of course, a population of H. erectus may have lingered undetected in Siberia. But if the divergence time is right, says Tyler-Smith, the new hominin cannot descend from that first migration into Asia 1.8 million years ago: Neandertals, the new hominin, and H. sapiens all share a common ancestor that lived 1 million years ago, presumably in Africa, according to the team. The new lineage could be related to H. antecessor, a species from northern Spain dated to between 800,000 and 1.2 million years ago and thought by some researchers to be the ancestor of H. heidelbergensis, says Chris Stringer, a paleoanthropologist at the Natural History Museum in London. Or it could represent “a pre-heidelbergensis, post-erectus dispersal” out of Africa “that we haven't picked up yet,” Stringer says.

Pääbo agrees that the new lineage might represent “something that came out of Africa later” than the first H. erectus migration. To find out more, his group plans to try to sequence nuclear DNA from the finger bone. If they succeed, they might discover the secret identity of Hominin X.

6. Research Funding

# NIH Seeks Fresh Ideas on Diversity

1. Jeffrey Mervis

The National Institutes of Health (NIH) is betting $10 million that academics can find new ways to promote diversity in U.S. science. The money will be spent on a new competition called the Director's Pathfinder Award. NIH is looking for a handful of researchers “willing to try something that would really change the game,” says Clifton Poodry of the division of Minority Opportunities in Research within the National Institute of General Medical Sciences (NIGMS), which will manage the program. “What haven't we been thinking about? What type of intervention or institutional change would take us to a new level?” The Pathfinder Award is modeled after the Director's Pioneer Award Program, begun in 2004, which generously funds individuals with potentially transformative research ideas. Pathfinder applicants must devote at least 30% of their time to efforts that will broaden the talent pool in the biomedical, clinical, behavioral, and social sciences. “We want their brains on the job,” says Poodry. “It's a bit of a gamble. We're betting on the person to do something great. It's like a MacArthur grant for diversity.” Freeman Hrabowski, president of the University of Maryland, Baltimore County, and a national leader in increasing minority participation in science, agrees that it's precisely those “great” individuals who can make the biggest difference in promoting diversity. “Whatever success we have achieved has had faculty involvement at its core,” says Hrabowski, who has nurtured the school's successful Meyerhoff Scholars Program. “Too often, tenured faculty are not involved in these kinds of activities.” The solicitation invites ideas at all levels, from precollege through faculty members, although Poodry acknowledges that most of NIH's programs in this area target graduate and postdoctoral students. Improving undergraduate retention rates is the key to promoting diversity, says Hrabowski, and requires innovations in teaching, curriculum, mentoring, and every other aspect of the educational process. The deadline for applications is 4 May. NIH plans an initial screening of the six-page proposals, followed by personal interviews of the finalists. It anticipates making five 3-year awards, for$2 million each.

The program is funded with money NIH received as part of the American Recovery and Reinvestment Act. That means NIH must commit the money by 30 September, and there is no provision for future competitions. But NIGMS Director Jeremy Berg suggested that NIH might continue the program with regular funding if the community's response is positive.

7. ScienceInsider

# From the Science Policy Blog

“Why So Few?,” a new report on women in science by the American Association of University Women, distills several recent reports on gender equity to provide a road map for those seeking improvements.

Three U.S. agencies have launched a joint program to predict climate change and its impacts on local scales over a few decades, fueled by $50 million a year for 5 years. A super-low-fuel navigation system for space flight, a software program that can recognize and analyze photos, and an exploration of mathematical representation theory snagged the top three awards at this year's Intel Science Talent Search. Physicist Carl Wieman, a 2001 Nobelist and a leader in reforming U.S. undergraduate science education, has been nominated to be associate director for science in the White House Office of Science and Technology Policy. Tim Berners-Lee and Nigel Shadbolt have received$45 million to create the Institute of Web Science, with the goal of helping the United Kingdom extract maximum benefit from the arrival of Web 3.0.

The spat over the leadership of the Royal Institution of Great Britain is headed to a showdown next month, with both fans and critics of former Director Susan Greenfield weighing in.

The U.S. National Institutes of Health is launching a new online registry that asks gene-testing companies to volunteer information on studies they've conducted on their products. The Genetic Testing Registry will be run by the National Library of Medicine.

For the full postings and more, go to news.sciencemag.org/scienceinsider.

8. Environmental Restoration

# Restoration or Devastation?

1. Dennis Normile*

A massive South Korean project to dam and dredge four major rivers has provoked bitter opposition from scientists and environmentalists.

YEOJU, SOUTH KOREA—A wetland a couple of hours'drive west of Seoul may be about as close as it gets to unspoiled nature in South Korea. Baweenupgoobi's 230-plus hectares of sand dunes and gravel bars hug a bend in the South Han River, whose clear, shallow waters join the North Han and flow through Seoul. In winter, the wetland is etched with ponds and rivulets; summer rains swamp the land, as evidenced by debris lodged high in willows. The habitat offers a niche for migrating waterfowl and unusual plants, including a rare type of chrysanthemum. “These plants have evolved in harmony with seasonal flooding, and the wildlife have adapted to it,” says Jeung Mingull, an ecological geneticist at Kongju National University in Gongju.

But the harmony may not last. Dams now under construction will turn the South Han into a chain of lakes. One end of Baweenupgoobi, supposedly a protected natural heritage site, has been stripped of vegetation to prepare for dredging; much of the rest will be under water. “The government calls it ‘river restoration,’” scoffs Jeung. Environmentalists mock the phrasing by calling it “river killing.”

The ecological transformation extends far beyond Yeoju. Launched last November, the government's Four Major Rivers Restoration Project calls for building 16 dams, dredging 570 million cubic meters of sand and gravel to deepen nearly 700 kilometers of riverbed, renovating two estuarine barrages, and constructing bike trails, athletic fields, and parks along the waterways. At $19 billion, it is one of the costliest engineering projects in the country's history. And it is attracting fiery opposition, notably from the Professors' Organization for Movement Against Grand Korean Canal (POMAC), a group of 2800 academics who accuse the government and supporters of twisting data and ignoring expert panel recommendations on issues such as water quality, flood control, rainfall patterns, and environmental impacts to justify a massive construction boondoggle. Both sides agree on one point: The project will dramatically transform the Han, Nakdong, Geum, and Yeongsan rivers. Four Rivers “will be an ecological disaster,” Jeung charged at a hearing in Seoul Administrative Court last month on an injunction to halt work on the South Han River. “[It] will be very beneficial for the environment,” countered Jae Park, an environmental engineer at the University of Wisconsin, Madison, and a rare academic who openly supports the government position. On 12 March, the court rejected the request for an injunction, but a suit to cancel the project is moving forward. Legal actions on the other rivers are pending. Winning even one of the suits “would be a major event in the history of the environmental movement in Korea,” says Lee Sang-don, a lawyer at Chung-Ang University in Seoul. ## Landscape architects Four Rivers is a pet project of South Korean President Lee Myung-bak, a former construction company executive nicknamed “the bulldozer” for his “can do” approach to engineering projects. One of Lee's signature accomplishments in his previous role as mayor of Seoul was to demolish an elevated highway to revitalize the Cheonggyecheon River. The river is far from natural: Water is pumped in from the Han, and it flows through a concrete channel. But its walkways, landscaping, fountains, and illumination provide an oasis in what had been a grimy industrial area. When completed in September 2005, the “restored” Cheonggyecheon was a huge hit with the public—and helped Lee win the 2007 presidential election. One of Lee's campaign pledges was to create a Pan Korea Grand Waterway by damming, dredging, straightening, and widening the Han and Nakdong rivers and connecting them by a canal carved through the peninsula's central mountains. Barges, he said, would be able to move 540 kilometers between Seoul, in the country's northwest corner, and Busan in the southeast. Lee promised that the waterway would take heavy trucks off roads, draw tourists to artificial lakes, and reinvigorate rural communities. Private investment and sales of dredged materials were supposed to cover the project's cost. Even before Lee took office on 25 February 2008, academics had challenged the data his team put forward to support the Grand Waterway. “It was truth versus falsehoods,” says Choe Young Chan, an agricultural economist at Seoul National University. Opposition mounted, and on 25 March, 2400 scientists, engineers, economists, and lawyers from the country's universities converged on Seoul for the inaugural meeting of POMAC. Using members' contributed expertise, the association pegged the project at double the cost that Lee estimated and found that sales of dredged materials would hardly make a dent in the cost. POMAC asserted that little freight moves between Seoul and Busan, and a survey of shippers turned up scant demand for a canal. The academics also questioned the project's claimed benefits for drinking-water supplies, rural economies, and the environment. Opponents got an unexpected boost a few weeks later when Lee announced that he would reopen South Korea's market to U.S. beef imports, which had been banned during a mad cow disease scare. That spring, farmer and consumer groups held candlelight protest vigils in major cities. Their ire expanded to encompass other unpopular policies, including the Grand Waterway. On 19 June, Lee announced he was abandoning the canal plan. Six months later, in December 2008, Lee unveiled a new scheme: Four Major Rivers. The “multipurpose project” will control flooding, secure water supplies, and create lakes for water sports as well as riverside parks for 1700 kilometers of bike trails and recreational facilities, says Je Hae-Chi of the Four Rivers project office. The government estimates Four Rivers will generate 340,000 jobs and$35 billion in long-term economic benefits. After a 3-month environmental assessment last summer, Lee's Grand National Party, which holds a majority in the National Assembly, pushed through enabling legislation. Lee wants the job finished before his 5-year term ends in early 2013.

Backers see the project as fixing a natural imbalance. The peninsula's seasonally shallow rivers and wide floodplains are a consequence of mountainous geography and weather patterns that bring two-thirds of annual precipitation during the summer. As a result, during winter, low water flows expose extensive gravel bars in riverbeds—“evidence of a water deficiency,” Je says. Dams will relieve flooding and water shortages, he says, by capturing water during the rainy season for release during dry months.

Touting the environmental benefits, Lee's administration has wrapped the project in a green mantle. River restoration is the largest component of the government's Green New Deal, a package announced in January 2009 to counter the economic downturn with stimulus spending that promotes sustainable development (see sidebar, p. 1570). It's “a totally different project” from Grand Waterway, says Hong Dong-gon of the Four Major Rivers project office.

To POMAC, however, the new plan is the Grand Waterway resurrected. The canal link through the mountains is missing, Choe says, but otherwise “the number of dams and their sites and the amount of dredging remains the same.”

Opponents decry what they see as unnecessary tinkering with nature. There is no question that flooding occurs on small rivers and tributaries far upstream of the planned dam sites. Instead of filling dams downstream and then building embankments and more dams on tributaries, as the government proposes, POMAC's Park Chang-Kun, a civil engineer at Kwandong University in Gangneung, says upstream flooding could be controlled by selectively raising riverbanks and employing other watershed-management techniques. Cities along the four rivers do not face water shortages, adds Choe.

As for environmental impacts, a draft report from Birds Korea, a Busan-based environmental group, notes that Ministry of Environment data and independent surveys show that the shallow braided streams “support a higher density of waterbirds per hectare than river-impoundments.” The report concludes that habitat loss from Four Rivers will affect about 50 bird species, some considered threatened. Fish, amphibians, and reptiles will also be affected, Jeung says: “Many riverine species will disappear.”

More fundamentally, some academics believe the plan reflects outdated thinking about watershed management. “The Four Rivers Project is out of step with the way river management is evolving in the developed world,” says G. Mathias Kondolf, a geomorphologist at the University of California, Berkeley. He says planners in Europe and the United States now aim to give rivers room to meander and flood. This approach is more ecologically sound, Kondolf says, and eliminates river maintenance imposed by dredging and embankments. Project official Hong counters that based on their research and case studies of rivers in South Korea, dams and dredging “is the best solution.”

## Reluctant activists

Experts who favor more ecological management of South Korea's rivers say their findings and recommendations have been steam-rolled by an administration that, in Park Chang-Kun's view, is “distorting scientific data for political purposes.” But from the government's standpoint, Je says, “people are in opposition for the sake of opposition.”

The list of those in opposition is growing—and includes most of the public. In a survey last October, before construction started, the Korea Society Opinion Institute reported that 26.4% of respondents wanted to see the Four Rivers Project canceled immediately; another 73.5% wanted it postponed until there was a social consensus. Dozens of South Korean and international environmental organizations have issued statements opposing the plan. And the Catholic Bishops' Conference of Korea published an instructional comic book that challenges the government on the Four Rivers Project for its “greed” and neglect of “the natural Created Order.”

Amid this wave of opposition, POMAC has played a crucial role by assessing the environmental and economic impacts of the government's plans, holding press conferences, and supplying the expertise underpinning the lawsuits. The multitude of scientists who have joined POMAC awes like-minded colleagues in other countries. “There is a long tradition of academics working with environmental or community groups as advocates, but I have never seen any numbers like these,” says Randolph Hester, an environmental planner at the University of California, Berkeley. The self-professed activist says that for community causes in the United States, “we can get three or four people to help us, and they might spend a week out of the year doing work for us. I've seen nothing like the commitment of this group.”

Even in South Korea, “such activism by academics is very unusual,” Jeung says. Politics often divide the community, but on this issue the Lee administration's policies “have brought conservatives and progressives together,” he says. They claim to be reluctant activists. “I hate to do this; I still have to publish and teach,” Choe says. Lee Won Young, an urban planner at the University of Suwon in Hwaseong, says he got called before his university's president to explain the time he has devoted to the cause.

The outcome of the battle over Four Rivers is up in the air. The ruling Grand National Party has blocked hearings on the subject in the National Assembly. Last month, the Democratic Party held its own hearings in which assembly member Kim Jinai outlined three scenarios for stopping the project. One is local elections in July; a trouncing of the Grand National Party could convince some assembly members to cross party lines on Four Rivers, he said. Another possibility is a construction-related disaster such as a spill of toxic chemicals that would make going forward politically impossible. The third barrier is the lawsuits. “I am confident we will win the final decision,” says Lee. But the “very complicated litigation” could last 2 years, he says. In the meantime, construction is going full throttle.

• * With reporting by Ahn Mi-Young in Seoul.

9. Environmental Restoration

# A 'Green' Blessing Raises Questions

1. Dennis Normile

The United Nations Environment Programme has been encouraging governments planning recession-fighting stimulus packages to support environmentally friendly projects and forge what UNEP calls a "Global Green New Deal." But critics charge that South Korea's Four Major Rivers Project is anything but friendly to the environment.

SEOUL—South Korea's controversial plan to transform the ecology of four rivers has become an improbable poster child of the Green New Deal movement.

## Guidelines for journals

The quickest action may come from the academic journals, which are moving toward adopting a common set of guidelines for studies using animals, says Sean Murphy of the University of Washington, Seattle, chief editor of the Journal of Neurochemistry. The checklist of 20 items, developed by the National Centre for the Replacement, Refinement and Reduction of Animals in Research in London, would require scientists submitting manuscripts to provide details including the sex of the animals used in their experiments. A manuscript describing the recommendations has itself been submitted for publication, and from there, “it's going to be straightforward for journals to adopt the guidelines,” he says. “They are sensible and will improve the quality of the papers.”

Still, Murphy feels that the guidelines don't go far enough to really shine a light on the importance of sex differences. At the IOM workshop, he wondered whether journal editors should also require authors to give their rationale for studying only one sex and describe the potential implications for not studying the other.

That would at least get scientists thinking about the issue of sex bias. Currently, few graduate or medical students are trained in sex differences, and many don't know how to work with female animals. But Clegg says she answers enthusiastic questions about working with females every time she gives a talk. She says, “People go back thinking, I wonder if I should pick the females up off the shelf and actually look at them.”

• * Chelsea Wald is a freelance science writer and editor in New York, New York, and Corinna Wu is a freelance science writer and editor in Oakland, California.

11. Biomedical Research

# Immunology Uncaged

1. Mitch Leslie

An immunologist argues that to move beyond mice and galvanize clinical research, his field needs its own version of the Human Genome Project.

With a routine blood test, your doctor can ascertain how well your metabolism handles lipids and whether you are vulnerable to heart disease. But don't expect to get a test that reveals whether your immune system is working normally or whether you are at risk for, say, autoimmune diseases. The reason: Researchers still can't define what's normal for the immune system, says Mark Davis, an immunologist at Stanford University in Palo Alto, California. Cardiologists can specify healthy levels of LDL, HDL, and triglycerides, but immunologists can't do the same for cytokines, key chemical messengers that trigger immune cells to mature, divide, attack, or perform other actions.

Researchers' reliance on mice deserves some of the blame for this ignorance, says Davis. No mouse-phobe, he keeps 400 cages of the rodents for studies of how T cells recognize pathogen molecules. But mice, says Davis, make a “lousy model” for the human immune system. The human and mouse lineages diverged some 65 million years ago, and the rodent's immune system has adapted to safeguard a small, short-lived animal that scurries around with its nose in the dirt.

However, nobody has cataloged the differences, and as a result, inconsistencies between human and mouse immunity often leave patients in the lurch, Davis says: “Hundreds of clinical trials have been based on curing mice, but almost none led to clinical treatments.” Take the case of myelin basic protein (MBP). Injecting MBP into mice causes a condition similar to multiple sclerosis, which can be prevented by doses of proteins that blunt the immune reaction to MBP. But clinical trials of these protective proteins were stopped because they made some people with multiple sclerosis worse.

Failures like that have spurred Davis to call for immunology to go big science in a very human way. If enough labs combine efforts to analyze the thousands of blood samples drawn in the United States or around the world every day, a so-called Human Immunology Project could quickly amass and scrutinize data from large numbers of healthy and sick people, Davis says. Within 5 to 10 years, he predicts, “we could have the first crude benchmarks of immune function.” Davis doesn't know what these benchmarks will be—perhaps the levels of particular cytokines or the abundances of certain types of T cells—but he says researchers will probably settle on five or six variables that reflect overall immune status in people, the equivalents of LDL, HDL, and triglyceride levels.

Davis is far from the first to point out the “mouse” problem in immunology. “Studies on mice are very elegant and beautiful, but they aren't reflecting the needs of the [human] population,” says Jacques Banchereau, head of the Baylor Institute for Immunological Research in Dallas, Texas.

Hoping to address this problem, Davis over 2 years ago helped to found Stanford's Human Immune Monitoring Center. HIMC analyzes blood samples mainly from Stanford clinical research labs but also from some biotech and pharmaceutical companies, says Director Holden Maecker. The center can measure levels of 50 cytokines, run microarrays to nail down gene activity, and gauge the abundance of more than 30 varieties of white blood cells using flow cytometry, a technology for counting and sifting cells. The researchers receive their results, but HIMC also stockpiles the data. Within a year or two, says Maecker, the center should have enough measurements from multiple studies to start nailing down what's normal for the immune system.

The U.S. National Heart, Lung and Blood Institute in Bethesda, Maryland, has established a similar facility, the Center for Human Immunology, Autoimmunity and Inflammation. The center, says Director Neal Young, provides access to technology, such as the latest flow-cytometry and gene-sequencing machines, that researchers at the National Institutes of Health (NIH) might not be able to afford or have the expertise to use. Many of these studies—a current one tracks the effects of the H1N1 flu vaccine on 200 NIH employees—will be “just looking,” Young says, and will accrue large amounts of basic immune data, which the center plans to make public.

Projects like these are a start, says Davis, but a concerted effort is needed. Large-scale projects are not only cheaper because of economies of scale, but they will also use standard procedures that yield comparable results. Moreover, squeezing the most information from blood samples will require an assortment of experts—from clinicians to bioinformatics virtuosos—who aren't available to every lab.

Banchereau is supportive of Davis's call. So is Ralph Steinman of Rockefeller University in New York City, who suggests that such a project could benefit one of his areas of interest: vaccines. “The truth is that to push vaccine science—say, for HIV or cancer—will require a major effort in human immunology.”

Davis's push for more basic research on human immunity has also impressed people who control the scientific purse strings. He's received grants for such work from the Howard Hughes Medical Institute and the Bill and Melinda Gates Foundation. And last year the U.S. National Institute of Allergy and Infectious Diseases announced that it would spend $100 million over five years on “human immune profiling research centers” that will track how our immune system responds to jolts such as vaccination and infection. The first grants are due to be awarded in May. A human immunology project would require more research like this—and more money. Although Davis hasn't submitted a formal proposal, he suspects that the bill would be in the hundreds of millions of dollars, much less than the$4.3 billion (in today's dollars) that the U.S. government spent on the Human Genome Project. Even some of the biggest fans of Davis's idea wonder, however, if such a project is affordable given the current economic climate. But unless we attempt to understand how our own immune system works, “we won't realize the health benefits of immunology,” Davis says. “It's not a sustainable strategy to stay focused on mice.”

12. Ecosystem Management

# Science Meets Politics Off California's Coast

Protecting marine resources involves a mix of cutting-edge science and political compromise, as California officials have learned.

Just offshore from San Diego, California, the largest kelp forest on the West Coast shelters rockfish, sculpin, and many other species. Anglers and sea urchin divers have plied those waters for decades, but not for much longer. The Department of Fish and Game is drafting regulations that would put 18 square kilometers off-limits to any fishing or harvesting. As a result, fish, lobsters, and urchins should start getting larger and more abundant, says Edward Parnell, a marine ecologist with Scripps Institution of Oceanography in San Diego. “They're going to fulfill their more historical ecological role,” he predicts.

The reserve is just one of 48 marine protected areas (MPAs) designated by a new plan, approved in December, that would safeguard 15% of the state waters off Southern California. Under an ambitious $38 million program that began in 2004, the state has already protected an even larger fraction of the Central Coast. Next up is the far northern reach of the coast. When the process is complete, California will have set aside more of its waters as no-take reserves than any other state, and perhaps as much as any country save Australia. “We've created an historic advance in marine conservation,” says Gregory Helms of the advocacy group Ocean Conservancy in Santa Barbara, California. Other countries are beginning to emulate the approach. But as the California experiment has shown, it's not easy. The process was authorized by a 1999 state law, the Marine Life Protection Act (MLPA), that called for a network of protected areas to rebuild and protect marine ecosystems. From the outset, scientists were heavily involved in figuring out the most effective locations for MPAs. After their initial efforts met with heated opposition, it became clear that the needs of the fishers had to be accommodated, too. So a political dance ensued and compromises were struck—especially in Southern California, where controversy has been most intense. The recently approved plan there is “not predicated on making the best network but on making the best possible bargain,” says Joel Greenberg of the Recreational Fishing Alliance. Not surprisingly, fishers are still worried about the economic impacts, and conservationists have been upset about the failure to protect the very best habitat in Southern California. But the disagreement among these warring camps has been eased by a new bioeconomic computer model for designing MPAs in a way that is most likely to maximize biological benefits while minimizing economic pain. It should be a useful tool, its creators say, for other nations that are setting out to protect their coastal waters. ## Networking During the 1980s, California's waters were generating worrisome headlines. Populations of rockfish and other fisheries were crashing, raising larger concerns about the condition of marine ecosystems. The state already had more than 100 MPAs before the passage of MLPA, but they were not carefully planned, says Satie Airamé of the MLPA Initiative, the public-private partnership that is running the process. The new law called for rigorous science to design MPAs that would function as a network to conserve marine life more effectively. The first attempt to implement the act failed miserably. In 2001, the Department of Fish and Game asked a team of eight scientists to create a draft map of proposed MPAs. When it was released for public comment, communities near the proposed reserves howled. “If you showed up wearing a tie or looking like a scientist, guys would throw shrimp at you,” recalls Christopher Weible, a public policy expert at the University of Colorado, Denver, who says it can take a decade to develop trust and work out details in designing an MPA. By the end of the year, the plan was shelved. A second attempt the next year included stakeholders but ran out of money. The process didn't really get going until newly elected governor Arnold Schwarzenegger added his considerable political momentum to marine conservation. Five foundations pledged$20 million to boost the state's funding, and the MLPA Initiative resumed work. The staff, drawn from various state agencies and nonprofit groups, divided the coast into four regions plus San Francisco Bay—a good move to reduce complexity, Weible says. The idea was to start in the Central Coast, learn from the experience, and then proceed to the next region.

First, however, a team of scientists created guidelines for the size and spacing of the protected areas. In a conceptual change from past efforts, the guidelines aimed to ensure that larvae could float from one MPA to another, based on estimates of how far they can travel. This would allow the populations in individual reserves to boost each other, creating a network of protected areas more resilient than if they were isolated. Another goal was to make sure that each kind of habitat was protected by more than one MPA. To meet these goals, 18% to 20% of state waters would need to be protected, says marine ecologist Steven Gaines of the University of California, Santa Barbara (UCSB), who helped craft the guidelines.

Next, the stakeholders got their turn. Anyone with an interest in coastal waters could participate: commercial and recreational fishing groups, for example, as well as marina operators and preservationists. Beginning in 2005, more than 50 representatives were charged to propose a set of networks in the Central Coast region. The proposals were reviewed by the science advisory team to check whether the networks met the guidelines for size, spacing, and habitat coverage. Then a Blue Ribbon Task Force, appointed by Schwarzenegger, forwarded the plans, along with a preferred alternative, to state officials for a final decision.

During the meetings on the Central Coast reserves, fishing groups had complained that the scientific advisory team didn't have an adequate number of fisheries scientists. So for the next section of coast, to the north, the MLPA Initiative recruited Ray Hilborn, a fisheries scientist at the University of Washington, Seattle, and others. Once involved, Hilborn expressed several concerns. Most fundamentally, he argued that there is no need to locate MPAs so that larvae can travel from one MPA to another, because plenty of larvae exist in between them. By establishing what he views as arbitrary guidelines based on larvae dispersal, the science advisory team had “manipulated the system to get a certain amount of state [waters] put in reserves,” he claims. Other members of the science advisory team disagreed, and the guidelines remained.

To help move past the debate, Christopher Costello, a UCSB economist on the science advisory team, and others wanted to focus on evaluating proposed MPA networks better. Costello, Hilborn, and Carl Walters of the University of British Columbia, Vancouver, in Canada developed a bioeconomic model that incorporates the habitat, ocean currents, and the biology of species, as well as fishing patterns. Another group, from UC Davis and headed by fisheries scientist Louis Botsford, adapted another model for the same purpose.

Rather than just pointing to guidelines, the models allowed the science advisory team to give much more explicit advice to stakeholders about the relative impact on conservation and fishing of placing MPAs in various locations. They could also project the costs and benefits of making a particular reserve bigger or smaller. The model was “worth its weight in gold,” says Helms of the Ocean Conservancy.

On the South Coast, the model helped negotiate the toughest point of contention: the Palos Verdes Peninsula just west of Long Beach. With the best rocky habitat in much of Southern California, the site was a top priority for preservationists. But creating a no-take zone there would cause big economic losses for charter fishing operations and restrict access by other users. When the political appointees on the Blue Ribbon Task Force decided not to protect the site, the model pointed to a second-best approach to conservation, emphasizing the need for MPAs around Malibu and Catalina Island, which had similar habitats. “The clearer you can be about what is at risk and why you're opting for one solution over another, the more acceptable the decision is,” says Margaret Caldwell of Stanford University Law School in Palo Alto, California, a member of the task force.

## Win-win?

The model hasn't eliminated controversy by a long stretch. Bob Bertelli, president of the California Sea Urchin Commission, thinks that the Costello model—as well as a social science survey commissioned by the MLPA Initiative—underestimates the economic impact of designating MPAs, noting that they only estimate the lost value from smaller catches. “All the information stops right at the dock,” he says, and ignores the larger effects on the community, such as businesses that cater to fishers.

Preliminary research raises the possibility of a better outcome. The bioeconomic model suggests that MPAs, if designed properly and coordinated with fishery management, could boost fishery profits. Costello and colleagues took data from the South Coast region and compared the outcome of fishery management with and without MPAs. The value of the fishery doubled for kelp rockfish, for example, when MPAs were located in places that produce a lot of larvae, they reported online 22 February in the Proceedings of the National Academy of Sciences. Hilborn and others are skeptical. “I think they're a long way from convincing people in the fishery management community,” Hilborn says.

Another unknown is whether the network of connected MPAs will perform better than a set of isolated protected areas would have. Marine ecologist Mark Carr of UC Santa Cruz says the only way to answer that question will be to use computer simulations, and it could take 10 years to get enough data. To help figure all this out, the California Ocean Science Trust, a nonprofit foundation, has pledged $16 million for monitoring the MPAs. Even before the California process is done and its effects tallied, other countries are taking note. “It's been watched globally,” says Jason Hall-Spencer of the University of Plymouth in the United Kingdom, a member of a scientific advisory panel now drafting ecological guidelines for a set of U.K. protected areas. “We're adopting many of the ideas.” 13. # Nations Move to Head Off Shortages of Rare Earths 1. Robert F. Service Looming scarcities of a handful of essential elements could shake the electronics industry, unless manufacturers and mining companies develop more sources soon. Picture the periodic table as a city. You've got your flashy downtown: gold, silver, and the like. You've got your industrial sector: iron and nickel. There are parks: carbon, oxygen, and nitrogen. And of course the “troubled” section: radionuclides. Then there are the forgotten, distant exurbs: the rare earth elements (REEs), lanthanum (element 57) through lutetium (element 71) along with scandium and yttrium. Sleepy no more, the exurbs have turned very desirable. In recent decades, REEs have become vital to a host of novel electronics and green-energy technologies. The trouble is that, while researchers are steadily inventing new applications for rare earths, the supply isn't keeping up—and users of REEs are feeling the pinch. Today, China supplies more than 97% of all REEs, and increasingly the products from which they are made. Those products span a wide swath, ranging from phosphors in electronic displays, to magnets in disk drives, cell phones, and MRI machines, and motors in missile guidance systems. In 2000, about 60,000 metric tons of rare earth oxide ores were mined worldwide. By 2014, that number is expected to grow to 200,000 metric tons. China's production of REEs has been growing steadily over the past decade. But because its domestic demand for the elements has been growing even faster, the country's REE exports have dropped from 75% of the total produced to 25% (see figure). For a handful of elements—neodymium, dysprosium, terbium, and yttrium—China is expected to use all it can produce sometime between 2012 and 2014, leaving the rest of the world out in the cold (Science, 11 September 2009, p. 1336). “We are going to have to start acting quickly, or we will be in big trouble,” says Ed Richardson, the sales and marketing manager for Thomas & Skinner in Indianapolis, one of the few makers of high-intensity magnets left in the United States, which relies on REEs to make its products. And with ever more applications on the horizon, Richardson says, “the problems we are seeing today are only going to get worse over time.” REEs aren't the only concern. Supplies of other metals vital to electronics and green technologies—such as indium and lithium—are also tightening as industrial uses for these materials skyrockets. Rare earths are not rare. They are ubiquitous in soils around the globe. But unlike gold and silver, which are heavily concentrated in particular ore deposits, rare earths are sparse. The world's richest veins of REEs contain only 4% to 9% of the elements. Most deposits have 1% or less of the elements—too little to make their processing economical, says Mark Smith, chief executive officer of Molycorp Minerals in Greenwood Village, Colorado, the only remaining rare-earth mining company in the Western Hemisphere. In some cases, mining companies are responding. For example, in the United States, Molycorp plans to reopen a mine in Mountain Pass, California, expected to produce up to 20,000 metric tons of rare earth oxides by 2012. In Canada, Great Western Minerals Group and Avalon Rare Metals hope to tap vast rare-earth deposits in Saskatchewan and the Northwest Territories. However, rare-earth mining consultant Jack Lifton notes that these companies have not been able to secure all the funds they'll need to start operations. New mining efforts are just the first step. Numerous rare earth oxides are invariably mixed together in ores. They must be separated and purified, reduced to metallic form, and then alloyed, cast, and shaped. All the Western businesses that used to do these extra jobs are gone and will need to be restarted. Setting up this full suite can cost hundreds of millions of dollars and take up to a decade to accomplish, Lifton says. That's enough to scare away most investors, who are interested in shorter term payoff. Investors also worry about a business that can be so easily manipulated by a single government, says Jeff Green, president of J.A. Green and Co., a government relations firm in Washington, D.C., specializing in rare earths. China seems unlikely to flood the market today, but it did just that in the 1980s and 1990s, driving most Western producers out of business. “It creates a really unstable investment situation,” Green adds. Green, Lifton, and others say plenty can be done to get over such hurdles. Last month, magnet industry leaders in the United States sent a letter to John Holdren, director of the U.S. Office of Science and Technology Policy in Washington, D.C., calling on the Obama Administration to take prompt action to restore rare-earth mining and processing in the United States and other Western countries. The recommendations included establishing short-term stockpiles of rare earths critical for defense needs and having the U.S. Department of Energy set up a$2 billion loan-guarantee program to help Western mining companies build new mining and processing facilities. Congress has already drawn up a bill to push such efforts, though it has yet to be introduced.

Such efforts could get a boost early next month when the Government Accountability Office (GAO) is scheduled to release an interim report on the vulnerability of defense applications to rare-earth shortages. If GAO determines that particular rare earths are vital to national security, it “could really get the ball rolling” in prompting government agencies to back REE mining and stockpiles, says Gareth Hatch, director of technology at Dexter Magnetic Technologies in suburban Chicago and editor of the RealMetalBlog.

Some manufacturing companies aren't waiting for U.S. and Canadian mining companies to take action. Toyota recently made a deal with a rare-earth mine in Vietnam, securing supplies of neodymium and lanthanum. In a single Prius, Toyota uses a kilogram of neodymium for its electric engine and 10 kilograms of lanthanum for its nickel metal hydride battery. In January, a Toyota supplier also formed a partnership with a mine in Argentina to supply lithium for batteries for its next generation of plug-in hybrid vehicles.

Lifton says other Western companies and governments need to act decisively, or they will find themselves frozen out of the market. “We have 3 to 5 years to get it done,” he says. “And we haven't even started yet.”

14. # Mission: Irreplaceable?

1. Robert F. Service

Scientists are scrambling to develop substitutes for scarce elements critical to industry. But the myriad uses of the elements make the effort an uphill struggle.

Scientists are scrambling to develop substitutes for scarce elements critical to industry. But the myriad uses of the elements make the effort an uphill struggle. “It's worthwhile to try and find replacements,” says Peter Dent, vice president for business development at Electron Energy in Landisville, Pennsylvania. “But it won't be easy.”

Dent's company makes high-powered magnets used in electrical generators. Magnets have increased in strength more than 100-fold over the past century—most dramatically in the 1970s and 1980s, when researchers added samarium and neodymium to magnet alloys. The rare earths fortify the alloys against outside magnetic fields, says Bill McCallum, a materials scientist at Iowa State University and Ames Laboratory in Ames, Iowa. Such fields can easily depolarize (demagnetize) a magnetic material such as iron, McCallum notes, because iron lacks strong “anisotropy,” or preferred orientation of its north and south magnetic poles. Adding neodymium, which has a strong anisotropy thanks to its electron structure, creates a much more powerful alloy. That property will be hard to replace, says Jack Lifton, a rare earths consultant in suburban Chicago, Illinois.

Nevertheless, researchers are trying. George Hadjipanayis, a physicist at the University of Delaware, Newark, says he and colleagues recently received funding to develop high-strength magnetic materials made from neodymium, iron, and boron nanoparticles that they developed in 2007. Neodymium-iron-boron magnets are the strongest conventional magnetic materials; mixing the elements at the nano-scale should yield at least as much magnetization with less neodymium, Hadjipanayis says. First, though, the team must make large three-dimensional collections of such nanoparticles and align their crystallographic axes—so far, a tall order.

Other efforts are further along. Solar cell makers have been working for years to perfect semiconductor alloys made from ultrathin films. The most successful use indium, the price of which has spiked to more than \$1000 a kilogram in recent years. Researchers have made alternative versions from abundant elements, such as copper, zinc, tin, and sulfur (CZTS). And last month, researchers at IBM reported in Advanced Materials that they had increased the sunlight-to-electricity efficiency of CZTS cells by 40%, to 9.6%—less efficient than indium-containing cells but close to the threshold of 10% considered critical for commercialization.

Researchers around the globe have also been toiling to replace indium used in transparent conductors in electronic displays. Last year, a team led by materials scientist Yang Yang of the University of California, Los Angeles, reported in Nano Letters that it had developed highly conductive transparent films by layering graphene (single-atom-thick sheets of carbon) and carbon nanotubes. The films aren't as good as ITO yet. But an analysis last year by Nano Markets, a market research firm in Glen Allen, Virginia, suggests that novel transparent conductors could soon find widespread use.

15. # Nitrides Race Beyond the Light

1. Robert F. Service

Long prized for their optical properties, nitrogen-based semiconductors may take electronic devices into realms where silicon cannot tread.

Sixteen years ago, Shuji Nakamura held up a few shining blue lights before a packed scientific meeting hall in San Francisco, California, and the audience oohed, aahed, and even produced a few groans. Nakamura—then a materials scientist with the Japanese chemical company Nichia and now with the University of California (UC), Santa Barbara—had created the first high-brightness, blue light–emitting diodes (LEDs), beating many of those in the room to the punch. That success paved the way for the blue lasers used in modern “Blu-ray” DVD players, as well as white LEDs that are now poised to usher incandescent light bulbs into the trash bin of technological history.

All of these gizmos were made possible by advances in making nitrogen-based semiconductors, known as nitrides. Nakamura's lasers and LEDs were made from gallium nitride (GaN) and other related semiconductor alloys. And advances in optical devices made from GaN continue at a rapid pace. Researchers in Germany and Japan reported last year, for example, that they had made the first ever green laser diodes from indium gallium nitride, an advance that could make possible a new generation of tiny full-color projectors. Researchers are reporting similar success with nitride-based electronic devices, including transistors that work at high speeds and at high temperatures, novel solar cells, and ultra-small chemical sensors.

“It's a very exciting time for nitride electronics, and the performance is increasing very fast,” says Tomas Palacios, an electrical engineer at the Massachusetts Institute of Technology in Cambridge. Such devices have the potential to outperform better-known silicon electronics for a wide range of applications.

One big reason for this versatility, Palacios and others say, is that—in contrast to most other semiconductors—the electronic behavior of nitrides can be tuned over a wide range. Semiconductors can act both as conductors—in which electrons move freely—and insulators, in which electrons are locked in. All semiconductors can be switched on to become conductors simply by adding extra energy. This kicks electrons from their locked state—known as the valence band—into their mobile state, or conduction band. The difference in energy between valence and conduction electrons is known as the material's band gap.

Silicon, for example, has a band gap of 1.1 electron volts (eV). Add that much energy and silicon's stationary electrons will hit the road. But if you'd rather have a silicon device with a higher band gap—which could be useful for making a more efficient solar cell whose band gap matches the energy of incoming photons, for example—you're stuck. Combining multiple cells, each tailored to capture a different part of the solar spectrum, typically produces more efficient devices overall. That's something the nitrides can accomplish. Indium nitride (InN) has a smallish band gap of 0.6 eV, GaN's is 3.4 eV, and aluminum nitride's is 6.2 eV. But three-part alloys, such as indium gallium nitride, can be adjusted to hit any band gap between InN and GaN by varying the amounts of indium and gallium. The same goes for the three-part alloy of aluminum gallium nitride. “This gives us a high flexibility to design new optoelectronic and electronic devices,” Palacios says.

Nitride semiconductors have other advantages as well. For starters, they're electron autobahns, allowing electrons to travel about four times as fast as in silicon. They are also extremely hard and able to withstand temperatures hundreds of degrees higher than silicon can, making nitride-based transistors and other devices better suited for a wide variety of applications such as electronics in automobile engines and devices that tailor the electrical voltages coming from the grid to particular appliances.

On the minus side, nitrides can be hard to work with, partly because researchers haven't yet developed an ideal substrate on which to grow them. Silicon electronics are grown atop pizza-sized wafers of single-crystalline silicon. But because there has been no robust way to make large single crystals of GaN, most nitride electronics are grown on substrates such as sapphire and silicon carbide, which have differently spaced atomic lattices and other drawbacks. As a result, Nakamura and others struggled for years to make GaN LED and laser diodes, because the GaN wound up riddled with cracks and other defects that interfered with the performance of the devices.

But recent advances suggest that help could be on the way. For example, over the past 2 years researchers from Ammono, a GaN company in Poland, say they have made bulk GaN substrate material using a process that grows the GaN from a seed material in high-pressure ammonia vapor. If the technique can be fully worked out, “it would be a major enabler of progress,” says James Speck, whose lab at UC Santa Barbara is working in the same area.

Meanwhile, progress in electronic applications is forging ahead on several fronts. One is the development of transistors capable of switching on and off at ultrahigh frequencies. Nitride high-frequency transistors are key to making amplifiers for satellite communications, radar devices, and cell phone base stations, Palacios says, because they are heat-tolerant, can send out large amounts of power, and can be made very small. In the March issue of IEEE Electron Device Letters, Palacios and colleagues report making the first-ever AlGaN/GaN high-electron-mobility transistors that can amplify signals at a frequency of 300 billion times per second, or 300 gigahertz. Today's cell phone base stations use amplifiers that work at a rate of about 1 to 2 GHz. So if the nitrides can be made to work as reliably, they could dramatically increase the speed of wireless communications. And the progress is not likely to end soon. “We think we are far from the limit,” Palacios says.

Nitride transistors might also prove essential for a variety of future “smart grid” applications. First, however, they must be able to withstand transmitting large amounts of power, something silicon-based electronics struggle with. In most nitride transistors developed so far for high-power applications, electrons can leak out of electrodes, causing power losses and even failure of the devices. In 2009, however, a team led by Lester Eastman, an electrical engineer at Cornell University, reported that by adding an insulating layer of hafnium dioxide to reduce leakages, they had made some of the first devices that can handle both high voltages and high current. “Before now, there were no electronic devices that could handle both high current and high voltage, but our device can do it,” Eastman says. If such devices prove to be reliable, Palacios says, they could make it far cheaper to control the movement of power through the electricity grid, enabling new energy production from solar and wind and new appliances that turn themselves during off peak hours of electricity demand.

In the longer run, nitrides might also prove useful in harvesting solar energy. To capture sunlight, solar cells use the energy in photons to kick electrons up from the valence band to the conduction band. In silicon solar cells, any energy a photon has in excess of silicon's band gap turns into heat and is wasted. But researchers such as Wladek Walukiewicz, a semiconductor physicist at the Lawrence Berkeley National Laboratory in California, hope the tunable band gaps of nitrides can change that equation. In a paper published online in Applied Physics Letters on 11 December 2009, Walukiewicz and colleagues report pairing a GaN solar cell with a more standard silicon cell, so that the GaN cell grabbed the higher-energy photons and the silicon cell grabbed those at the lower end of the spectrum. The team didn't measure how efficiently the device converted sunlight into electricity, but Walukiewicz says such GaN and Si tandem cells could someday outperform standard silicon cells by 50%.

A final area in which the nitrides are poised to make a big impact is as highly accurate chemical sensors. Nitrides are chemically more inert than most other semiconductor sensors, says Fan Ren, a chemical engineer at the University of Florida, Gainesville, and their high electron mobility means they generate less noise and thus can spot smaller signals. That means that they can be made smaller, more sensitive, and more cheaply than other sensors. Six years ago, Ren says his team made its first nitride-based sensors to detect hydrogen fuel leaks for NASA; car dealers later adapted them to check tanks storing fuel for hydrogen-powered cars.

Ren's group and others have also tailored nitride-based transistors to detect DNA, changes in pH, and even proteins associated with breast cancer. In the January Journal of Diabetes Science and Technology, Ren and colleagues reported that by coating key regions of an AlGaN-GaN transistor with a glucose-binding enzyme called glucose oxidase, they could use it to detect glucose in subjects' breath. Similar sensors might provide a noninvasive way to track a diabetic's glucose levels. Such applications have long seemed fanciful, but progress in nitride-based electronics is bringing them steadily closer.