News this Week

Science  26 Nov 2010:
Vol. 330, Issue 6008, pp. 1162
  1. News Analysis

    New Republicans Could Revise Party Line on Research Funding

    1. Jeffrey Mervis

    Since the midterm elections, U.S. science leaders have been reassuring their community that Republicans traditionally have been very supportive of basic research. As proof, they point to statements from Newt Gingrich, former speaker of the House of Representatives, that his biggest failure after the 1994 Republican takeover of Congress was not pushing through a tripling of the National Science Foundation (NSF) budget.

    But the new House leadership, due in part to the success of Tea Party activists, is quite different from its predecessors. And that difference could put a damper on hopes that the next Congress will deliver on a long-promised expansion of federal spending on research and education outlined in a 2005 National Academies' report that has been embraced by both parties. Here's why.

    "What I hear from new members is that ‘we love science, but we are coming to Washington to cut the budget.' Well, to that I say, ‘When you're designing a plane and trying to save weight, you don't throw out the engine.' "

    —NORMAN AUGUSTINE, CHAIR, RISING ABOVE THE GATHERING STORM PANEL

    CREDIT: PAUL E. ALERS/NASA

    The day after Republicans reclaimed the House of Representatives, their second-in-command, Representative Eric Cantor (R–VA), spelled out what's changed. "Perhaps the single greatest criticism of our previous majority," Cantor explained in a 22-page governance plan, "is that we spent too much and that we grew the size of government." (His emphasis.) Those mistakes were a result of ignoring "our core Republican principle of limited government," Cantor noted before adding, "We're not the same Republican Party."

    Of course, limited government and reduced spending are not what Norman Augustine, former CEO of Lockheed Martin, and the other authors had in mind in their influential 2005 report, Rising Above the Gathering Storm. Instead, they called for a $19-billion-a-year increase by 2013 in the federal investment in research, education, and innovation to keep the United States competitive in a global economy. "Actions such as doubling the research budget are investments that will need to be made if the nation is to maintain the economic strength to provide for its citizens' health care, social security, national security, and more," declares a recent, 5-year update of the original report that deplores the lack of progress toward its goals.

    The 2005 report offered four major recommendations. The request for more research spending received the most attention—in particular, a 10%-a-year increase in the budgets for NSF, the Department of Energy Office of Science, and the National Institute of Standards and Technology and the creation of the Advanced Research Projects Agency–Energy within DOE. But an even higher priority for the panel was expanding the federal role in training new science and math teachers and improving the skills of those already in the classroom. [The President's Council of Advisors on Science and Technology (PCAST) recently fleshed out some of those approaches to improving elementary and secondary education (Science, 24 September, p. 1582)]. The report also recommended ways to attract more U.S. students into science and engineering, and changes in immigration and patent policies so that U.S. companies can compete more effectively in world markets. In other words, it said, a healthy U.S. innovation climate requires more spending and a larger role for government.

    The report was requested by a bipartisan coalition of legislators in a Congress controlled by Republicans, and its words provided the basis for the 2007 America COMPETES Act. Science lobbyists invoke both the 2005 academies' report and the 2007 legislation, which is up for reauthorization this year, as evidence of bipartisan support for basic research. And they have extrapolated that attitude to the 112th Congress that will convene in January with a sizable Republican majority in the House and a reduced Democratic presence in the Senate. Some science advocates also speculate about a left-right consensus that would yield big increases for energy research.

    But all that may be wishful thinking. "The nation's outlook has worsened. … Our public school system has shown little sign of improvement, particularly in mathematics and science," complains the updated Gathering Storm report, subtitled Rapidly Approaching Category 5. There are more, not fewer, constraints on the nation's capacity to innovate, it notes, resulting in a decreased ability to provide good jobs. Although the report doesn't say it, that deterioration occurred despite 4 years of a Democratic Congress whose most visible leader, House Speaker Nancy Pelosi, had a simple prescription for healing the country's ailing economy: science, science, science, and science.

    Nobody's expecting any such focus on science from the new speaker, Representative John Boehner (R–OH), or any of his leadership team. Neither Cantor's statement nor the more visible Pledge to America that the party issued during the fall campaign even mentions science, research, or education. The only reference to "innovation" comes as part of a passage in the Pledge on how "excessive federal regulation … hampers innovation and postpones investment in the economy." In other words, get the government off our backs so that the private sector can do its thing.

    As a former captain of industry, Augustine is comfortable in the company of those making such arguments. "I'm a registered Republican, although I try to remain nonpartisan," he says. "I've spoken with most of the key players. And I agree that there are lots of places where the federal budget can be cut."

    What worries Augustine is the idea that everything should be on the chopping block. "What I hear from new members is that ‘we love science, but we are coming to Washington to cut the budget.' Well, to that I say, ‘When you're designing a plane and trying to save weight, you don't throw out the engine.' The biggest threat to innovation is this army of pickaxes that want to sweep away everything, including research."

    "The single greatest criticism of our previous majority is that we spent too much and that we grew the size of government. We're not the same Republican Party."

    —ERIC CANTOR, THE NEXT HOUSE MAJORITY LEADER

    CREDIT: HOUSE REPUBLICAN CONFERENCE

    Such broad cuts would devastate the U.S. science enterprise, says Chuck Vest, the president of the National Academy of Engineering and a member of both the 2005 and 2010 panels. Briefing PCAST on the updated report a few days after the election, Vest warned that tough times are ahead and cited the report's opening line from physics Nobelist Ernest Rutherford: "Gentlemen, we have run out of money. It is time to start thinking." If the panel's recommendations remain unheeded, he added, another update in 2015 could begin with an even darker forecast, which he attributed hypothetically to John Holdren, science adviser to President Barack Obama: "Gentlemen, we have run out of money. It is time to start drinking."

    What the Republicans are thinking may not be visible during the lame-duck Congress. The chief item of business is a spending bill for the remainder of the 2011 fiscal year, which began on 1 October. If Democrats try to wrap all 12 appropriations measures into one omnibus package, several science agencies could receive some portion of the increased spending that Obama requested in his February budget submission to Congress. More likely, however, is a further extension of 2010 levels.

    Reauthorization of the 2007 COMPETES bill before Congress adjourns would strengthen the hand of the Obama Administration in any upcoming battles with Republicans over science spending. But prospects for the bill, which passed the House in May, seem dim. "The vote [in 2007] was not at all partisan," notes Representative Rush Holt (D–NJ), a former physicist and strong advocate for the bill. "But I'm afraid that some Republicans see it as a Democratic initiative that grew out of the speaker's innovation agenda. That would be enough of a reason to oppose it."

    Whatever happens in the next few weeks, the Republican campaign for a smaller government is expected to kick off in earnest in January. And if advocates for continued federal investments in research and education are blown out of the water, the culprit may be a Category 5 electoral hurricane.

  2. Drug Research

    Roche Exits RNAi Field, Cuts 4800 Jobs

    1. Jennifer Couzin-Frankel

    The Swiss drug company Roche announced last week that it is stepping away from research in RNA interference (RNAi), a popular approach to medical therapies and one that Roche has poured more than $400 million into over 3 years. The decision is part of a plan to reduce Roche's workforce by 6%, or 4800 people.

    CREDIT: ROCHE

    Although it's not unusual to see contractions in big pharma, Roche's decision to abandon work in RNAi is striking because the field has gotten much attention. The technique, which earned a Nobel Prize in 2006 (and Science's Breakthrough of the Year in 2002), involves using tiny RNA molecules to shut down specific genes. But getting them to diseased tissues in the proper dose has challenged scientists. The field is “fascinating, but unfortunately this delivery point is a hurdle,” says Claudia Schmitt, a Roche spokesperson. The 50 or so employees at Roche's RNAi “Center of Excellence” in Kulmbach, Germany, most of them scientists, were just not able to overcome that stumbling block, she adds.

    No RNAi drugs are on the market yet; one for macular degeneration failed in late-stage trials last year. But more than a dozen clinical trials are under way in cancer, asthma, and other conditions. “People are going to look at this Roche thing and … be less enthusiastic” about RNAi, says Mark Kay, a gene therapist at Stanford University in Palo Alto, California, who's been working with the technique in hepatitis C. That would be a shame, Kay argues. A veteran of bitter setbacks in gene therapy, he wasn't expecting RNAi to advance nearly as rapidly as it has, and he still considers it promising.

    Delivering RNAs to target tissue remains tough, although researchers are making progress. Chemically modifying one strand of the double-stranded small RNAs has reduced off-target effects, such as the molecules' unnerving propensity to hit too many gene sequences (Science, 12 November 2004, p. 1124). This may also ease another glitch: Depending on how they're packaged, the RNAs and their delivery vehicle together can stimulate the immune system in dangerous ways. “You are going to run into technical barriers,” says Kay. “It takes time to solve them.”

    Like many other pharmaceutical companies, Roche was in a tight spot, with a bet that wasn't about to pay off. Even if RNAi pans out, it isn't likely to offer a windfall in the next year or two. “The easiest things to let go are things that have long-term perspectives,” says John Maraganore, the chief executive officer of Alnylam, an RNAi biotech company in Cambridge, Massachusetts. Roche formed a collaboration in 2007 with Alnylam, which once owned the German site now impacted by cuts. Alnylam currently has three RNAi drugs in clinical trials.

    Other large drug companies remain invested in RNAi, for now at least, including Merck, Novartis, and Takeda.

  3. ScienceInsider

    From the Science Policy Blog

    The British government has apologized for postmortem research done on nuclear plant workers without proper consent in a report that blames British pathologists for ethical lapses in scores of research projects carried out from the 1950s to the early 1990s. An official inquiry launched in 2007 notes that the work generated important data.

    A series of ill-advised decisions by operators to save time and money likely contributed to the eventual blowout and explosion that oiled the Gulf of Mexico this year, says an expert panel that found nothing inherent in deepwater drilling or the geology of the offshore oil and gas reservoirs that would have doomed the Deepwater Horizon. One example, it says, was relying on a newly installed cement plug in the well despite the plug having failed three successive tests.

    A budget impasse is jeopardizing a hard-won compromise on how to handle Europe's share of additional costs for the international ITER fusion reactor. ITER chief Osamu Motojima discussed with Science this week his plans to create a larger optional reduction without creating technical risks. The details must be worked out in the next few months to keep ITER on track.

    ScienceInsider provided a continuously updated, blow-by-blow account of a climate change hearing, attracting hundreds of viewers and comments. Billed as a “rational discussion” of the issue by the House of Representatives science committee, it was a farewell performance for Democrats before the Republicans assume control of the panel in January.

    Croatian scientists are up in arms over a set of new policies instituted by the science ministry last month. The policies include merging the research and higher education “councils” and eliminating an ethics body altogether. The ministry says it is reviewing more than 1000 comments.

    For more science policy news, visit http://news.sciencemag.org/scienceinsider.

  4. Paleontology

    Excavation Yields Tantalizing Hints of Earliest Marine Reptiles

    1. Richard Stone

    CHAOHU, CHINA—Eons ago, convulsions warped the land here on the edge of town, thrusting slabs of mudstone and limestone high into the sky. Buried in the rock are traces of a mass extinction that wiped out about 90% of oceanic life forms and brought the Paleozoic era to a shuddering close 251 million years ago—the end of the Permian period and beginning of the Triassic. When life rebounded in the early Triassic, a new kind of top predator arose: ichthyosaurs. Marine reptiles would dominate the oceans until another mass extinction ended the Cretaceous 65 million years ago.

    The origins of marine reptiles are an enigma. Their ancestors came from the land, but scientists can only imagine what sort of animals ventured into the sea and evolved into the three successful lineages of marine reptiles: sleek tuna-shaped ichthyosaurs; sauropterygians, including the long-necked plesiosaurs; and mosasaurs, which gulped down prey with double-hinged jaws like those of snakes. “The invasion must have happened very fast, within 4 million or 5 million years after the end of the Permian,” says paleontologist Jiang Da-yong of Peking University in Beijing. But the fossil record of this ocean colonization is largely a blank slate. “We have very little material from the lower Triassic,” says Olivier Rieppel, a specialist on Mesozoic marine reptiles at The Field Museum in Chicago, Illinois.

    Rescue paleontology.

    Ryosuke Motani (left) and Jiang Da-yong hope to unearth spectacular marine reptiles before farmers do.

    CREDIT: R. STONE/SCIENCE

    Answers may be entombed at Majiashan quarry, in a 150-meter-thick outcropping dappled with shades of gray that spans 6 million years of geologic history. “We expect to find new species here,” including forms marking the land-sea transition, says Ryosuke Motani, a paleontologist at the University of California, Davis, who, with Jiang in September, launched the first systematic excavation at Majiashan. The dig's first fruits—including an ancestor of the plesiosaurs—are already generating a buzz.

    Majiashan, north of Chaohu City in central China's Anhui Province, is a fixture on the paleontological map. In 1972, railway workers here found an unusual fossil that two scientists at the Institute of Vertebrate Paleontology and Paleoanthropology in Beijing—Young Chung-chien and Dong Zhi-ming—identified as a new species of ichthyosaur, Chaohusaurus geishanensis. Since then, a couple dozen more Chaohusaurus skeletons from the early Triassic have streamed out of this site and nearby Guishan; most were unearthed by quarry workers and farmers, and most have ended up in private collections. Besides looking more like land reptiles than other ichthyosaurs, Chaohusaurus was about 70 centimeters long—much smaller than ichthyosaurs from the late Triassic and the Jurassic, which could top 15 meters in length.

    Motani and Jiang have their eyes on a bigger prize: undiscovered pint-sized marine reptiles, presumed to be tens of centimeters long, with vestigial limbs, or other terrestrial features such as lungs and ears better adapted to life on shore. “We hope to find the oldest marine reptiles. Then we'll look for signs of their ancestors,” says Jiang. Worldwide, few outcroppings from the Permian-Triassic boundary, the beginning of the Mesozoic era, are as promising as Chaohu. “This is where the fossils have to be,” says Nick Fraser, a paleontologist at National Museums Scotland in Edinburgh. “But you still have to get lucky to find them.”

    The first fossil fragments of a marine reptile—those of an ichthyosaur—were unearthed at the turn of the 18th century. The species drew scientific interest only a century later, in 1811, when a 12-year-old girl collected the skull and vertebrae of Temnodontosaurus platyodon on the Dorset coast in England. Mary Anning became one of the great fossil hunters of all time. Among her many other discoveries is the first fossil of a plesiosaur, Plesiosaurus dolichodeirus, which she found in 1821. The creature was so unlike living animals that it helped convince skeptics that species could go extinct—a new and not widely accepted concept at the time.

    Since then, several dozen species of extinct marine reptiles have come to light, mostly members of the three dominant lineages. Ichthyosaurs, soon after arising in the early Triassic, morphed into a variety of body plans. It took about 20 million years, however, for plesiosaurs—four-flippered behemoths resembling overgrown sea lions—to have evolved from early sauropterygians. The ancestors of mosasaurs, which arose in the late Cretaceous, are entirely obscure, as is the kinship of a less-known fourth lineage of marine reptiles, the lizard-like thalattosaurs of the middle to late Triassic, which appear in the fossil record from 247 million to about 200 million years ago.

    Researchers are beginning to get a handle on the physiology of these beasts. Recent findings suggest that ichthyosaurs and plesiosaurs—which cruised for food—were warm-blooded, allowing them to maintain constant muscle activity (Science, 11 June, p. 1379; p. 1361 depicts evolutionary relationships between Mesozoic marine reptiles). Mosasaurs were ambush predators more like crocodiles, their body temperature matching that of the water.

    Plenty of questions about early Mesozoic marine species remain unanswered, and Anhui holds particular appeal as a possible source of information. During the Triassic, two large oceans intersected in this region: the Panthalassa, which covered half the globe, and the Tethys, which gave rise to the Indian Ocean and the Mediterranean Sea. Bivalves from both oceans have been found in Early Triassic sediments in Chaohu, Motani says.

    On an exploratory trip to Majiashan in September 2008, Jiang tracked down farmers and quarry workers who had collected fossils from the site and was shown some intriguing specimens. “The farmers called them all Chaohusaurus, but it's clear that some are other kinds of reptiles,” Jiang says. The skeletal fragments were too big to be Chaohusaurus; in Jiang's estimation, they represent at least two new species.

    Fine pedigree.

    Majiashan is famed for Chaohusaurus, an early diminutive ichthyosaur.

    CREDIT: COURTESY OF JIANG DA-YONG; RYOSUKE MOTANI

    The researchers are racing to recover more of these treasures, but time is not on their side. Over the years, quarry workers at Majiashan have gouged deeply into the Permian-Triassic boundary formation. “We only have this much limestone,” says Motani, gesturing to an outcropping with spray-painted red splotches indicating layers that have been dated. “When it's gone, the early Triassic is gone.” But his team has a big advantage: The geological layers here are stacked like books on a shelf, which makes it possible to survey millions of years of rock without climbing high. And specimens can easily be carted out after excavation.

    To protect the site, the Chaohu government has vowed to close the quarry and the nearby cement factory it supplies, says Jiang. And to cut down on illegal fossil sales, his team, working with Jiang Li-ai, director of Anhui Geological Museum in Hefei and president of the Paleontological Society of Anhui, plans to educate residents and local authorities about the fossils' scientific value.

    Back in Beijing, Jiang Da-yong has begun analyzing the specimens pried from the rock in September. They include the remains of a new kind of early ichthyosaur and skeletal fragments of a sauropterygian that was less than a meter long—a tiny ancestor of the mighty plesiosaurs. “It's exciting,” says Rieppel. “We are all hoping for more!”

  5. ScienceNOW.org

    From Science's Online Daily News Site

    Evolutionary Relationships Hold, Even in Our Guts The human body is coated with bacterial cells. They live on our skin and between our teeth. They particularly like our warm, nutrient-filled gut, where they help digest food, make vitamins, and produce some seriously smelly gas. But when it comes to these gut bacteria, we are not what we eat. A new analysis of feces from humans and several other primates, published in PLoS Biology, finds that evolutionary history, not diet, determines the makeup of our intestinal bugs.

    Spacecraft Successfully Returns Asteroid Dust For the first time, a spacecraft has landed on and returned samples from a celestial body other than the moon. Last week, ecstatic Japanese officials confirmed that dust retrieved from the capsule of its Hayabusa spacecraft did indeed come from the asteroid Itokawa and is not earthly contamination. The microscopic bits had been under investigation since the capsule landed in the Australian outback last June after a trouble-plagued, 7-year roundtrip to the lumpy, potato-shaped asteroid.

    CREDIT: COURTESY OF AKIHIRO IKESHITA/JAXA

    Fish Sleep Soundly in Mucous Cocoons Even the ocean has bedbugs. Tiny bloodsucking crustaceans roam the seas, nipping at the scales of passing fish. But the parrotfish (Chlorurus sordidus) has evolved an unusual defense. Researchers report in the Proceedings of the Royal Society B that the fish spend up to an hour—and 2 % of their daily energy budget—spinning cocoons from their own mucous before they settle down to slumber for the night. These transparent, gelatinous balls of spit are large enough to envelope the fish from head to tail. Researchers showed that fish sleeping without protection were 80% more likely to be bitten by the crustaceans.

    Read the full postings, comments, and more at http://news.sciencemag.org/sciencenow.

  6. Bioethics

    Oversight But No Strict Rules for Synthetic Biology

    1. Jocelyn Kaiser

    A presidential bioethics commission concluded this week that the U.S. government should not clamp down too hard on research on synthetic biology, a young field that it says doesn't yet pose serious risks. Instead, the commission will recommend better coordination of research and ongoing reviews to see if rules should be updated.

    Formed in April, the 13-member Commission for the Study of Bioethical Issues' first assignment was prompted by a report in Science: the insertion of a synthetic genome into a bacterium by a team led by biologist J. Craig Venter (Science, 21 May, p. 958). In July and September, the panel heard from various experts about the concerns and potential benefits of that development and other types of synthetic biology (Science, 16 July, p. 264).

    The commission met last week in Atlanta to wrap up a report due on 15 December. Members emphasized the need to strike a balance between what they called “letting science rip” and the precautionary principle of waiting until all risks are understood, explains co-chair Amy Gutmann, president of the University of Pennsylvania. Although the chances are low that an organism made with synthetic biology will be accidentally released, such an accident could have a big impact, the panel concluded. So the draft report calls for “prudent vigilance”: encourage research while monitoring the field and updating regulations as needed.

    Open door.

    Gutmann wants dialogue about risks.

    CREDIT: UNIVERSITY OF PENNSYLVANIA

    Such oversight could be done by a coordinating committee that reports to the White House Office of Science and Technology Policy. It would evaluate government funding and conduct a “gap analysis” of existing regulations, as well as review the need to revise patent and data-sharing policies.

    The panel's 19 draft recommendations include some specific advice. New synthetic organisms should be marked so they can be tracked if they escape into the wild and should be made wimpy so that they couldn't spread. Biosafety training should extend to engineers and others doing synthetic biology. The commission is also concerned about public perceptions—many media reports inaccurately suggested Venter had “created life,” Gutmann notes. She says the report will suggest that a nonprofit group create a Web site for examining biotechnology claims along the lines of Factcheck.org, which corrects misstatements by politicians.

    The commission agreed that the government should keep an eye on an estimated 2000 amateur synthetic biologists, known as Do-It-Yourselfers (DIYers). Federal officials might eventually want to require that everyone comply with rules such as the National Institutes of Health's guidelines for studying recombinant DNA even if they don't receive NIH funding. But the panel decided against any immediate mandates that could drive the hobbyists underground. Instead of “us versus them,” the commission wants the DIYers “to be invited to the table,” says Gutmann.

    “The direction they're taking seems to me to be the right one,” says ethicist Thomas Murray of The Hastings Center in Garrison, New York.

  7. National Institutes of Health

    Collins Endorses Merger of U.S. Addiction Research Programs

    1. Jocelyn Kaiser

    The National Institutes of Health (NIH) will likely dissolve its two institutes that study drug and alcohol abuse and combine their programs. In a statement last week, Director Francis Collins said he had received a formal recommendation from an NIH advisory board to create a single “new institute” to study substance use, abuse, and addiction.

    The proposal “makes scientific sense,” Collins said. A task force will figure out by next summer how to carry out the effective merger of the National Institute on Drug Abuse (NIDA) and the National Institute on Alcohol Abuse and Alcoholism (NIAAA).

    Collin's decision is controversial. The $462 million NIAAA budget is less than half that of the $1.06 billion NIDA, yet it funds a slightly higher proportion of submitted grants. Alcoholism researchers and patient advocates are worried that their smaller institute will be swallowed up and that certain studies, such as research on alcoholism-related liver disease, will be cut short. The NIAAA council voted unanimously earlier this year against a merger; NIDA's council members all voted in favor.

    According to the advisory panel's report, the new institute would also house the National Cancer Institute's tobacco addiction programs. And nonaddiction research would go elsewhere—for example, NIAAA's research on fetal alcohol syndrome would likely be transferred to NIH's child health institute.

    Critics of the plan say they're concerned that the problem of alcohol abuse will lose visibility with both the public and the research communities. Robert Messing of the University of California, San Francisco, says alcoholism research was “a backwater” before NIAAA was created but now attracts many young scientists. Former NIAAA Director Enoch Gordis says “I believe it's not a good idea” because it ignores scientific differences between alcohol and drug addiction and the fact that alcohol kills far more people than drugs. “I just hope it doesn't do any damage.”

    The notion of combining the two institutes was suggested by a National Academies panel in 2003. But it was not until Congress created a Scientific Management Review Board (SMRB) in 2006, aimed at examining NIH's structure, that things began to happen. In September, an SMRB working group recommended either combining NIDA and NIAAA in a new institute or better coordinating addiction research across NIH. The full board voted 12-3 in favor of the new institute.

    It's not a done deal, however. Secretary of Health and Human Services Kathleen Sebelius has to approve the merger plan and then notify Congress, which will have 180 days to intervene.

  8. Neuroscience

    New Clues About What Makes the Human Brain Special

    1. Greg Miller

    What differentiates the human brain from those of our nearest primate relatives? Size, for one. Our brains are more than three times bigger than those of chimpanzees. But many researchers have come to suspect that less obvious differences lurking in the fine-scale structure of the human brain also contribute to its extraordinary processing power (Science, 2 March 2007, p. 1208). Identifying such microscopic differences has been a challenge, however.

    Now, researchers who've examined preserved samples of cerebral cortex from humans and several species of ape say they've found some intriguing clues about what makes the human brain unique. They report that in a particular region of the prefrontal cortex, an area that contributes to abstract thinking and other sophisticated cognition, neurons have more space between them in the human brain than in the brains of apes. This extra space allows more room for connections between neurons, explains Katerina Semendeferi, a physical anthropologist at the University of California, San Diego, who led the new study along with graduate student Kate Teffer. More complex neural wiring presumably allows more complex information processing and, in turn, more complex cognition, Semendeferi says. The findings were presented last week at the annual meeting of the Society for Neuroscience in San Diego and published online this week in Cerebral Cortex.

    “For me, it's very interesting,” says Pasko Rakic, a neuroscientist at Yale University. Rakic notes that much of what distinguishes humans from other apes is the type of social behavior mediated by the prefrontal cortex. “This is the area where we have to look for differences.”

    Teffer, Semendeferi, and colleagues examined preserved brain tissue from all six living species of the hominid family, including eight humans, three chimpanzees, two bonobos, one gorilla, three orangutans, and two gibbons. The ape brains came from animals that died of natural causes at zoos or at a primate research center.

    After slicing the brain tissue into ultra-thin sections, the researchers selected four regions of the cortex for closer study. Three of these areas specialize in what might be considered more routine functions: the primary visual cortex (which makes sense of what we see), the primary somatosensory cortex (which handles information about the sense of touch), and the primary motor cortex (which helps plan and execute movements). The fourth area, called Brodmann area 10 (BA10), sits at the pole of the frontal lobes, just above the eyes, and is thought to be involved in more complex types of thought. A debate has simmered over whether the frontal cortex as a whole is proportionally larger in humans than in other primates, but Semendeferi has reported previously that the BA10 subregion does seem to be expanded in humans.

    The team used two methods to assess the spacing between neurons in the four areas of the cortex, based on images captured by a camera attached to a microscope. In one approach, a computer program measured the horizontal distance between cell bodies, which appear as dark dots in the images (see above). Most neurons have a characteristic shape: a bloblike cell body with many protruding branches. These are the axons and dendrites that send and receive messages from other neurons. In the second approach, the computer calculated the proportion of the total area of an image that was occupied by cell bodies. As the spacing between cells increases, the horizontal distance increases and the area occupied by cell bodies decreases.

    Take a look.

    More space between neurons in the human brain (right) compared with the chimp brain (left) could allow more complex neural wiring.

    CREDITS (TOP TO BOTTOM): KAREN HUNTT/CORBIS; K. SEMENDEFERI, CEREBRAL CORTEX (ADVANCE ONLINE PUBLICATION) © 2010 OXFORD UNIVERSITY PRESS

    According to both measures, there were only subtle differences among the six species in the visual, somatosensory, and motor cortices. The frontal lobes told a different story, however. In the human brain, cells in BA10 were more widely spaced than they were in any of the other apes.

    “It's a well-done piece” of work, says Bob Jacobs, a neuroanatomist at Colorado College in Colorado Springs. “It's another in a long line of findings showing there's something special about the human frontal lobes.”

    Those findings include the observation that the dendrites of neurons in the human frontal cortex branch in more elaborate patterns than do those in other primates, as well as the observation that human frontal cortex, including BA10, contains a higher concentration of so-called Von Economo neurons, which some researchers believe are a type of high-performance neuron specialized for rapidly transmitting information from one brain region to another.

    Because the new study focused specifically on the layer of the cortex that gives rise to connections between regions of cortex, the findings suggest that neurons in the human frontal cortex may also be more interconnected with their counterparts in other regions of cortex, says Chet Sherwood, an evolutionary neuroanatomist at George Washington University in Washington, D.C.: “They're going to be able to do computationally greater things because they're integrating more inputs.” But Sherwood says the study leaves open the question of whether this wiring pattern arose as a direct result of natural selection or as a side effect of brain expansion in the human lineage.

    Not everyone is impressed with the study, however, Manuel Casanova who studies brain evolution at the University of Louisville in Kentucky, sees a host of methodological problems, including the small number of samples, the way the tissue was prepared, and the algorithms used to measure the distances between cells. “It really seems to be a preliminary study whose conclusions may not generalize,” he says.

    Sherwood agrees that the study has some limitations, but he doesn't think they're serious enough to discard the findings. “I think there is a story there,” he says. “There is a consistency with some of the other data, which gives it that whiff of repeatability.”

  9. Bacteria and Asthma: Untangling the Links

    1. Jennifer Couzin-Frankel
    Bugs galore.

    We all harbor bacteria, but asthmatics host different species, including Staphylococcus aureus.

    CREDIT: DAVID SCHARF/SCIENCE FACTION/CORBIS, DRPH/CDC

    Six years ago, Gary Huffnagle, an immunologist at the University of Michigan, Ann Arbor, conducted an experiment that reflects what happens to many of us early in life. He exposed mice to a triple whammy: yeast in their intestines, mold spores up their noses that migrated down the airways, and an antibiotic drug. The animals began showing signs of asthma; blood tests revealed disruption of their immune systems.

    “They developed some fairly wicked allergic disease in the lung,” says Huffnagle. The mold and yeast alone didn't make much difference. “The bottom line is, those animals are perfectly healthy until we hit them with an antibiotic.”

    Huffnagle's study, published in 2004 in Infection and Immunity, was one of the first pieces in a dizzying new jigsaw puzzle of asthma, whose causes remain elusive even as the number of cases is soaring. Researchers have some striking clues: For example, children on farms are much less likely to get the lung disease. “A rich microbial environment in childhood is somehow protective,” says William Cookson, a respiratory physician and geneticist at Imperial College London. Cookson and others are now moving from the outside environment to deep in the body, exploring whether bacteria there might influence the onset of asthma.

    Sterile birth.

    C-sections, which expose babies to fewer bacteria than vaginal births, are linked to a higher risk of asthma.

    CREDIT: ISTOCKPHOTO

    As odd as this might sound, there's mounting evidence that bacteria matter. Babies born via cesarean section, who experience a more sterile entry into the world than those born vaginally, are more likely to get asthma. So are young children treated with many courses of antibiotics. Along with animal studies, these observations suggest that the balance of bacteria and other microbes help guide immune development—and that when the balance is disrupted, disease may follow.

    The picture can be dishearteningly complicated. Thousands of species of bacteria have constructed virtual cities inside us, along with fungi and viruses—a world called the microbiome. And it's not so much the presence or absence of bacteria, or even certain species, that matter, but rather the shape of the whole community. All of us play host to bacterial residents. But children who develop asthma, researchers are learning, are home to different bacteria—and sometimes a less diverse mix—than those who stay healthy. “It's really coming down to the bacterial community structure, who's there, and in what numbers, and where,” Huffnagle says. Cataloging these inhabitants is a new frontier.

    Lungs and guts

    For many years Hans Bisgaard, a pediatrician at the University of Copenhagen, was puzzled by a classic feature of asthma: Very young children with the disease have abundant neutrophils in their lungs, white blood cells that generally appear when the body is fighting infection. Given that asthma isn't considered an infectious disease, this reaction seemed out of place.

    Beginning in 2000, Bisgaard had a chance to assuage his curiosity. He and his colleagues were recruiting about 400 pregnant women with asthma to track the onset of disease in their offspring. They took throat swabs from the babies when they were 4 weeks old and looked for certain pathogenic bacteria. To their great surprise, about a fifth harbored these microbes in their airways, including strains of influenza and pneumonia.

    The newborns weren't sick and so were left untreated. Five years later, 33% of those who had had pathogenic bacteria early on had asthma—compared with 10% of those without the bacteria. The work was published 3 years ago in The New England Journal of Medicine. “It's redefined our course of research,” says Bisgaard. His team has since launched a second cohort study, this one of 800 pregnant women, most of them healthy, and has found the same prevalence of airway bacteria in newborns.

    The work also upended how researchers think about lung biology. “If you read a medical textbook even now, it will say the lungs and the airways are sterile; there aren't any bacteria down there,” says Cookson. He became certain that the conventional view was incorrect when he and an Imperial College colleague, geneticist Miriam Moffatt, conducted their own variation of Bisgaard's study in babies. They had at their disposal advanced gene-sequencing techniques that allow for a much more comprehensive census of bacteria flourishing in the lungs. In January, the two and their colleagues wrote in PLoS ONE that they'd sequenced more than 5000 different species in 43 people, including some with asthma and others who were healthy.

    Hay protects.

    Youngsters on farms are less prone to asthma and allergies, but it's not clear why.

    CREDIT: GREHAN FARRELL/CORBIS

    The bacterial balance was quite different in the asthmatics: Affected children had more proteobacteria, which include pathogens like influenza. A different class—bacteria called bacteroidetes, found in soil, seawater, the gut, and skin—were more common in the nonasthmatics. Cookson and Moffatt are now collaborating with Bisgaard to conduct gene sequencing of lung bacteria in Bisgaard's Copenhagen cohort.

    Similar discoveries may help explain the association between birth by C-section or abundant antibiotic use and increased risk of asthma in childhood. In Dutch research published in 2008, 8-year-olds born by C-section had nearly double the risk. Both C-sections and antibiotics modify the flora of gut and possibly lung bacteria, in some cases for many years. “The microbiota of children born through C-section is different; it's less diverse,” and the same is true for antibiotic use, with fewer species present, says Anita Kozyrskyj, an epidemiologist at the University of Manitoba in Winnipeg, Canada.

    And just as Cookson found different bacteria in the lungs of asthmatics, there's growing evidence that this is true in the gut, too, says Fernando Martinez, a pediatric pulmonologist at the University of Arizona, Tucson.

    Researchers are probing the connection with animal work and following thousands of children from birth. A Canadian effort called CHILD is recruiting 5000 pregnant women and will track their children for at least 5 years. “We have lots of poop frozen away”—including the newborn's first, right after birth—“dust from the babies' beds, nasal swabs, [a] massive library of this information that we'll be able to piece together,” says Stuart Turvey, a pediatric immunologist at the University of British Columbia in Vancouver, one of CHILD's leaders.

    So far, the evidence linking asthma and bacteria are associations, not proof that an imbalance of bacteria causes the disease. The big question, says Martinez, is, “Do asthmatics have an immune system that makes them be colonized by different things? … Or is it because they were colonized by different things that caused them to have asthma?”

    From the inside out

    Even less is known about what might be modifying lung and gut microbial communities and why children exposed to the same factors respond differently. The pattern isn't clear-cut: Many children born vaginally, or who never got antibiotics, still develop asthma, just as many born by C-section or given antibiotics do not.

    One piece of the puzzle is likely to be genetics: Some babies may be more prone to colonization by certain microbes, or to developing asthma once that colonization occurs. Another piece is the environment. For years it's been known that children raised on farms are less likely to develop asthma and allergies than others. This phenomenon is often referred to as the “hygiene hypothesis,” the idea that the relatively germ-free lifestyle most of us now lead can disrupt the development of the immune system.

    In the countryside of five European countries, Erika von Mutius, a pediatrician and epidemiologist at Munich University Children's Hospital in Germany, is sifting for clues. She and others are planning to sequence stool samples and throat swabs from more than 1100 children—half on farms and half in nonfarm rural settings. They're also collecting samples of milk (farm milk is often unprocessed) and the components of dust for limited gene sequencing. “A lot of this is inhaled,” and because we're talking about young children, “a lot of this is also probably ingested,” says von Mutius.

    Although researchers assume that a child's microbiome is affected by the environment, they don't know this for sure. And proving definitively that bacteria help cause asthma is remarkably difficult. “The only proof lies in a randomized controlled trial, where you somehow manipulate exposure” and see who gets sick, says Bisgaard.

    Researchers are experimenting with this approach in the gut. Probiotics, microorganisms like Lactobacillus found in yogurt, could in theory be helpful, but small trials testing whether they prevent allergic disease haven't been definitive. In 2006, the University of California, San Francisco, began recruiting about 200 babies who have at least one parent with asthma. Half receive a probiotic and half get a placebo, and the researchers are focusing on early markers linked to asthma, like eczema and wheezing. In January, they reported that 6 months of probiotics in infancy did alter the balance of microbes in the babies' guts, but final results are several years off.

    However these studies turn out, there's no question that asthma has diverse triggers. Huffnagle's mice needed a series of insults—gut yeast, antibiotics, and mold—to cause an explosion of symptoms. If the bacterial communities living in children wind up high on the list of risk factors, that may help solve one of the biggest mysteries of all in asthma: why the number of cases has climbed so high, and how it might be pulled back down.

  10. Conservation Biology

    The Fight for Yasuni

    1. Eric Marx*

    A group of scientists is on the verge of winning its battle to protect an Ecuadorian forest containing record biodiversity—but will the world pay to seal the innovative deal?

    Protected park.

    Beneath this forest canopy lies a record-setting number of species.

    CREDIT: © BEJAT MCCRACKEN, BEJAT.COM

    In 1997, 25 years after the first of many childhood canoe trips with his father down Ecuador's lower Napo River to the Limoncocha Biological Reserve, David Romo returned to find the site trashed beyond recognition. Once a pristine habitat fiercely defended by indigenous hunter-gatherers known as Waorani, the reserve had been overrun by a settlement of farmers who had moved in after construction of an oil-access road. The Waorani were gone, and so were many of the species that had made up the reserve's acclaimed biodiversity. Nowhere were once-common birds such as the grey-winged trumpeters and harpy eagles. The colonists had decimated the lake's fish and caiman populations, and poaching and tree-cutting felled the last primary forest in the area. “The forest was completely destroyed,” Romo, a conservation biologist at Ecuador's San Francisco University of Quito, recounts with dismay.

    Not long after Romo's unhappy return, the lure of oil threatened to bring similar devastation farther south to Ecuador's Yasuni National Park and the adjoining Waorani Ethnic Reserve. In 1989, this 17,000-kilometer section of the Amazon Basin had been designated a UNESCO Biosphere Reserve. But it also happens to sit atop Ecuador's second largest reserve of crude oil, a block of concessions collectively known as the Ishpingo Tambococha Tiputini (ITT) field. In 2003, that rich prize spurred plans to build a new oil-access road into the park, instilling fears of a repeat of what happened in Limoncocha. “I realized then that we needed to bolster our conservation efforts with good, credible science if we were to have any chance of saving Yasuni,” says Romo.

    Multimedia

    View a slideshow of Yasuni's diverse species.

    . . .

    Over the past decade, he and more than 50 other biologists working in the area have documented Yasuni's remarkable biodiversity, providing evidence that its forest has the highest number of species on the planet, including an unprecedented core where there are overlapping world richness records for amphibians, reptiles, bats, and trees. And after helping to form a group called Scientists Concerned for Yasuni, Romo and his colleagues have waged an international campaign to protect the location.

    This unabashed science-based advocacy has had an impact. In 2005, the year after the group published a preliminary analysis of Yasuni's biodiversity and recommended its protection, Ecuador's government rejected further road-building inside the park. Two years later, Ecuador President Rafael Correa went even further, offering a proposal in which his country would, in exchange for several billion dollars, keep the ITT oil permanently under ground in order to protect the park and to fight global warming. Industrialized countries would essentially pay to keep the park's oil-derived carbon in the ground.

    After several years of political negotiations and drama, the innovative initiative took a significant step toward reality this summer when the United Nations agreed to oversee a trust fund paid to Ecuador for the project. If all goes according to plan, the initiative may serve as a model for preserving intact biodiversity in other oil-rich portions of the western Amazon. But that's a big “if”: President Correa has vowed to allow drilling if the international community fails to compensate Ecuador sufficiently.

    Finding “megadiversity”

    The magnitude of Yasuni's species richness first became evident in 1992 when the Maxus oil company hired botanists to salvage plant specimens during construction of a new road entering the northwest section of the park, which borders Colombia and Peru. It was a thrilling and yet exceedingly difficult task, recalls Nigel Pitman, a tropical biologist at Duke University in Durham, North Carolina, who in 1999 completed an inventory of 1500 different species of trees. “Getting familiar with the trees can take years,” says Pitman, “and even then it means making up your own names for the dozens of species that are new to science. … It isn't even diversity any longer—it's hyperdiversity, or megadiversity.”

    But if field inventories were beginning to reveal the forest's extreme diversity, no one in the 1990s was synthesizing the voluminous, unwieldy mass of independently conducted plot-based studies into an overall picture of Yasuni's biodiversity. “People came to this area to do their research and left,” says Holger Kreft of the Georg-August University of Göttingen in Germany, who has found that among lowland forests, Yasuni holds the record for most species of epiphytes: plants that grow on plants. “There wasn't anything approaching a network of scientists.”

    That changed after 2003 when the Brazilian national oil company Petrobras announced plans for a new 54-kilometer road into an isolated section of the park that would give access to the ITT oil fields. It was already clear that the Maxus road had provided an entry point for people to colonize the forest and for illegal logging in the park's northwest section, says ecologist Matt Finer, whose Yasuni postdoctoral research quickly shifted to campaigning once he discovered little if any organized opposition to Petrobras's new plans.

    To conservation biologist Margot Bass, the announcement by Petrobras, one of the largest companies in the world, seemed like an irrevocable death sentence for Yasuni park. “I despaired,” says Bass, an executive director of Finding Species, a small environmental group, who had worked in the park in the late 1990s.

    Nevertheless, she and Finer, now with the Washington, D.C.–based environmental group Save America's Forests, rallied together a who's who of leading tropical ecologists, organizing a 2-day conference in October 2004 at which attendees detailed the biodiversity significance of Yasuni and illustrated how the previous Maxus road had spurred deforestation. The researchers followed up with intense lobbying. “This was not pure science,” says Luis Suarez, head of Conservation International's Ecuador office, who was not part of the group. “They decided to take a position and produce not only a scientific paper but also write letters, give presentations, and basically put Yasuni on the agenda.”

    Despite scientific and legal challenges, Petrobras began road construction and was on the verge of entering the park when, at the end of April 2005, President Lucio Gutierrez was deposed after massive protests of his plans to revamp Ecuador's Supreme Court. By July, the new government had revoked the oil company's permit for the road. Soon thereafter, President Correa stepped forward with his ITT proposal. “We kept so much heat on the issue that it gave bigger and better funded organizations time to try and put together a really systematic plan for the region,” says Bass.

    A Copenhagen setback

    In the 3 years since Correa floated the Yasuni trust fund plan, oil exploration has progressed nearby—in eastern Ecuador and across the border in southwest Colombia and northern Peru—and scientists working at Tiputini Biodiversity Station, one of two university-affiliated research stations in the park, say it's as if an unstoppable force is closing in. “Tiputini is still very remote,” says Christian Voigt, an animal behavioral physiologist, “but you can hear the generator of an oil platform from a few kilometers' distance, and at night you can see the glow of the gas flame.”

    Yasuni's advocates have pressed on with amassing proof of its biodiversity riches, hoping such data will persuade the international community to pay for the park's protection. In January, Bass, Finer, Kreft, Pitman, and their colleagues published a data-rich, collaborative analysis in PLoS ONE that confirmed the existence within Yasuni of a so-called quadruple richness center. This 28,000-km2 plot encompasses peak species records for amphibians, birds, mammals, and tree communities. “Yasuni is probably unmatched by any other park in the world in total number of species. Both our species-distribution maps and our comprehensive analysis of existing field inventories support this finding,” says Bass.

    Make a deal.

    If paid billions of dollars, Ecuador will prevent oil exploration in Yasuni.

    CREDIT: M. TWOMBLY/SCIENCE

    The area around the Tiputini station, for example, has smashed the world record for local amphibian diversity, with its 139 species far exceeding the 98 documented in Leticia, Colombia, the previous record-holder. And for insects, Yasuni's estimated 100,000 species per hectare represents the highest biodiversity, per unit area, in the world for any taxonomic group.

    Those who have made Yasuni their research home, and their mission, expected that Correa's initiative would get off the ground at the Copenhagen climate summit last December. But the Ecuadorian government questioned whether it had enough authority over the trust fund, and no deal was struck then, infuriating the country's environmental and scientific communities. “There was, already, Germany committing $50 million per year for 10 years,” an angry Romo recalled this spring, hands waving in the air. “We had letters of intent from at least five other countries—and now you say you want to go to OPEC and ask them for the money. That's betrayal!”

    Emotions have cooled since then, and in August Ecuador signed an agreement enacting the governance arrangements on a deal to keep Yasuni oil fields untapped in exchange for a minimum $3.6 billion in payments (about half the value of the oil if sold) from industrialized countries over the next 13 years. The United Nations Development Programme, which will oversee the trust fund, has suggested that the agreement could serve as a model for protecting ecosystems around the world.

    However, numerous questions about the effort remain, particularly in regards to the composition of the government-dominated board tasked with dispensing the trust fund's monies for conservation and reforestation projects, sustainable energy development, and livelihood-training programs for the local indigenous communities. There are fears, for example, that indigenous representatives will be excluded from the decision-making process.

    The biggest uncertainty remains funding. Chile has already committed $100,000, and Ecuador's vice president had said that Belgium, Spain, Turkey, and China have also offered money. But no official pledges from those countries have been announced, and in September, Germany signaled it was rethinking its vital commitment of nearly one-sixth of the needed total. If $100 million isn't paid into the United Nations fund by December 2011, Ecuador can refund any contributions—and analysts say Correa will then surely move to develop Yasuni's oil fields.

    Although he's nervous about whether the international community will fill the trust fund, Romo says he believes that the Yasuni researchers have so far succeeded in a way that cannot be ignored, providing justification for the region's continued conservation. “What caught the world's attention is the science,” says Romo. “But the clock is running and we cannot get distracted.”

    • * Eric Marx is a freelance writer based in Berlin.

  11. Stem Cells

    Diseases in a Dish Take Off

    1. Gretchen Vogel

    Michael Venuti wants to rearrange the process of drug discovery. Usually patients enter at the last step, he says, in clinical trials. But as the CEO of iPierian, a biotech company in South San Francisco, Venuti is hoping to change that. Using reprogrammed stem cells taken from patients, iPierian and others are starting to develop lab models of disease that give researchers “a look at the patient in a dish,” he says. “Although we're not putting patients themselves into the process, we are introducing them earlier than they have ever been included in the history of drug discovery.”

    These advances are not the miracle cures some expect to come from stem cells: regenerated organs or a cure for diabetes. Such therapeutic advances are far in the future, experts agree. But ever since the first human embryonic stem cells were isolated, scientists have dreamed of using them to study intractable diseases.

    Finding answers.

    Scientists are reprogramming cells from diseased patients, using them to better understand the disease process and search for new drugs.

    CREDIT: M. TWOMBLY/SCIENCE

    That dream, says Kevin Eggan, a stem cell biologist at Harvard University, “is a reality. It is the early days of that reality.” There are still plenty of hurdles, but already researchers have shown that reprogrammed cells from patients with a handful of rare genetic disorders can provide new clues about how the diseases do their damage. In several cases, the cells have pointed toward promising new treatments.

    The turning point came with the 2006 discovery that adult cells could be reprogrammed to an embryolike state simply by adding a handful of genes to the cells. The reprogrammed cells, called induced pluripotent stem (iPS) cells, have transformed the stem cell field. Not only do they get around many of the ethical issues that have dogged human embryonic stem cells, but they have also made it possible for researchers to make a ready supply of pluripotent cells from patients whose disease they are studying. (Pluripotent cells have the potential to become any cell type in the body.) The technology “made it so accessible for labs to get into the stem cell field,” says Gustavo Mostoslavsky, a stem cell scientist at Boston University School of Medicine. “For the first time, we have the ability to take any disease that is out there, take a few cells from a patient, and create pluripotent cells in a dish,” he says. “I think we will see an explosion of papers in the next few years.”

    Already, dozens of labs around the world are making iPS cells from patients and coaxing the cells to become the tissues that are affected by a given disease, for example, neurons from patients with amyotrophic lateral sclerosis (ALS). Researchers are comparing the ALS cells' behavior with that of nondiseased cells to tease out what could be killing the patients' neurons. Companies are using heart cells derived from iPS cells to screen drugs for possible cardiac side effects—a common problem (see sidebar, p. 1173). Others are planning “virtual clinical trials” to test thousands of new drug candidates, using panels of dozens of cell lines from patients and from healthy controls.

    The first successes in using iPS cells to study a disease in a dish have involved relatively rare genetic conditions that involve just a single gene malfunction. Nearly 2 years ago, at the University of Wisconsin, Madison, Clive Svendsen, now director of the Cedars-Sinai Regenerative Medicine Institute in Los Angeles, California, and his colleagues reported that they had derived iPS cells from a patient with spinal muscular atrophy (SMA), a genetic disease that strikes children, often killing them by age 2. To develop a useful disease model, the researchers needed to prompt the iPS cells to make the affected tissue and then show that the cells exhibit characteristics of the disease in culture.

    SMA was a promising candidate. Scientists knew how to grow motor neurons from embryonic stem cells, and they knew, in principle, how to cure the disease. (SMA has been called “the most curable neurological disease for which there are no treatments.”)

    SMA patients have a faulty copy of a gene essential to the survival of motor neurons called Survival Motor Neuron 1 (SMN1). Because their cells don't make enough of the SMN1 protein, their motor neurons die and patients become paralyzed. People also have a gene called SMN2 that makes the same protein but in much smaller amounts. Some SMA patients have multiple copies of the SMN2 gene, so they have milder symptoms and commonly survive into their 30s or 40s. The goal, then, is to find a drug that triggers the SMN2 gene to make more protein.

    Because mice and other common model animals lack the SMN2 gene, it has been difficult to develop an animal model that truly reflects the human disease. And although scientists have used human skin fibroblasts to screen for compounds that boost SMN protein production, the cells don't seem to produce or use the protein in the same way as do motor neurons. With iPS cells, scientists had their first chance to study large quantities of motor neurons that carried the disease's genetic defect.

    As a control, Svendsen and his colleagues also made iPS cells from the SMA patient's mother, who was unaffected by the disease. Initially, both cell lines behaved similarly, making healthy-looking motor neurons. But after a few weeks in culture, the SMA cells started to falter, with fewer and fewer neurons growing—the first sign that the cells reflected the disease phenotype. To see whether the cells would respond to potential drug candidates, scientists added two compounds known to boost SMN production. The model worked: The diseased cells produced up to three times as much SMN protein as their untreated counterparts.

    Several groups are building on the work, screening hundreds of thousands of compounds on Svendsen's cells as well as new lines from other SMA patients to search for possible drugs. iPierian is focusing on SMA, and early screens have been promising, Venuti says, turning up compounds that seem to work preferentially in motor neurons.

    Another example is the rare genetic disorder called familial dysautonomia (FD). Developmental biologist Lorenz Studer at the Sloan-Kettering Institute in New York City and his colleagues derived iPS cells from patients with FD, a disease in which the peripheral neurons degenerate. The researchers described in Nature in September 2009 how they prompted the FD iPS cells to form neural crest precursor cells, known to be affected by the disease. (The neural crest forms in early development and gives rise to facial bones, smooth muscle, peripheral nerves, and other tissues.) The cells from FD patients expressed significantly lower levels of the genes involved in neuronal development and formed fewer neurons than control cells. These cells, too, passed the crucial disease-model test: When the scientists treated the cells with kinetin, a plant hormone known to affect the gene implicated in FD, the FD cells made more of the missing protein and formed more neurons. Exposing cells to the hormone for several weeks had the greatest effect, an observation that could be important to the design of early clinical trials of kinetin in FD patients, Studer says.

    Proof of principle.

    Neurons derived from patients with spinal muscular atrophy (right panels) increase the production of a key protein when treated with a potential drug (bottom panels).

    CREDIT: A. EBERT ET AL., NATURE 457 (15 JANUARY 2009)

    Studer and colleagues have developed ways to make hundreds of millions of cells, with a robot distributing them onto the test plates, and are using them to screen thousands of compounds. The scientists are also comparing cells from patients with early- and late-onset disease to see if they can understand the delay in symptoms. “Studer is really pushing the field forward,” says Eggan.

    Some genetic syndromes may help scientists understand much more common diseases as well. This month, Alysson Muotri, a neurobiologist at the University of California, San Diego, and his colleagues reported in Cell that iPS cells from patients with Rett syndrome form neurons that have multiple defects compared with control cells. Rett patients develop normally for 6 to 18 months, but then lose muscle control, develop seizures, and show increasingly autistic behavior. Muotri and his colleagues hope that the model could help scientists to understand better what goes wrong in other autism spectrum disorders.

    Several groups have made iPS cells from patients with genetic heart defects, including long QT syndrome, which can cause deadly arrhythmia, and LEOPARD syndrome, a disorder involving thickened heart muscle and other defects. The cells are far from a perfect model of more common heart disease, says developmental biologist Christine Mummery of Leiden University Medical Center in the Netherlands. But given the dearth of animal models for that major killer, the cells are a promising step, she says.

    Dozens of labs are working with iPS cells from patients with more common conditions, including Parkinson's, ALS, schizophrenia, and Alzheimer's. But those diseases will be tougher to study. They result from a mix of genetic and environmental factors, and it is not yet clear how well iPS cells will reflect the environmental history of the cell donor. Still, the chance to work with unlimited quantities of cells derived from patients with these diseases is unprecedented. Until recently, Eggan says, “we haven't had a way to get at diseases that are sporadic but obviously have a genetic component.”

    Stem cell researcher James Thomson of the University of Wisconsin, Madison, cautions that researchers don't yet fully understand the variation in iPS lines. If two lines behave differently, it is difficult to tell whether that is because of disease-relevant genetic differences or random differences introduced in the reprogramming process, although newer techniques are helping. Studer agrees. “The big question in the field is variability” in reprogrammed cells, he says.

    Despite the challenges, more diseases are going to yield their secrets using iPS cells, Eggan predicts. “It's going to happen. It's just hard work.” Considering that reprogramming technologies are less than 5 years old, he says, “it's hard not to be pretty pleased with the progress that's been made in a few short years.”

  12. Stem Cells for Sale

    1. Gretchen Vogel
    CREDIT: CELLULAR DYNAMICS

    Dozens of biotech companies hope to use stem cell technologies to make products that turn a profit, but very few have. Cellular Dynamics International (CDI), based in Madison, Wisconsin, is an exception. CDI sells cardiomyocytes—heart muscle cells—derived from induced pluripotent stem (iPS) cells for $1500 per vial. Each vial contains about 1.5 million frozen cells, enough to fill a 96-well plate with beating heart cells that survive longer than 2 weeks in culture, says Chris Parker, CDI vice president and chief commercial officer.

    There are plenty of buyers. Parker says several dozen pharmaceutical companies are already using the cells to screen new drugs for side effects that affect the heart, one of the most common reasons otherwise promising candidates fail.

    The standard tests for these side effects use animal cells, cancer cells with an introduced heart gene, and dogs. “It takes roughly $2 billion and 10 years to get a drug to market—and despite that we are still getting drugs on the market with cardiac side effects” that later have to be withdrawn, says Christine Mummery, a developmental biologist at Leiden University Medical Center in the Netherlands. She and her colleagues were some of the first to demonstrate that cardiomyocytes derived from human embryonic stem (ES) cells could predict a drug's side effects.

    Cardiomyocytes often form spontaneously in human ES cells or iPS cell cultures that are left to differentiate on their own. But getting large quantities of pure, mature cells has been a challenge. CDI's scientists have managed to find ways that prompt industrial-scale quantities of iPS cells to develop preferentially into heart cells. They also developed a cell-sorting technique that results, Parker claims, in a cell population that is “99% cardiomyocytes.” Cardiomyocytes don't divide, so the cells are a “consumable product,” he says. The company guarantees that they will beat in culture dishes for at least 2 weeks. “So far so good,” Parker says. “We haven't had anyone send their vials back.”

  13. Preserving African Cultural Heritage

    Archaeologists, or Activists?

    1. John Bohannon
    Empowered.

    Locals are included in an archaeological excavation in Lesotho.

    CREDIT: JESS MEYER

    When Charlie Arthur started his archaeological work in the small southern African country of Lesotho in 2008, the clock was already ticking. The Phuthiatsana River valley is set to be flooded by a dam in 2012, submerging a rich record that includes Paleolithic tools and beautiful rock art. If this dig was going to be like previous ones in the region, the University of Oxford archaeologist would have zipped in and out with a minimum of interaction with local people and hauled the artifacts back to the United Kingdom. But despite the time pressure, that's not what happened.

    First, Arthur's team invited schoolchildren to learn about the ancient tools and rock art in their neighborhood. They trained locals, who were soon maintaining sites on their own. They arranged to donate equipment to local institutions and started a newsletter in the native language. They even appeared on television. Without this approach, says Arthur, “no benefit at all would come to the local heritage structures or communities under threat from the dam.”

    The Lesotho project was one of dozens involving engaged archaeology presented at Cheikh Anta Diop University here earlier this month. The Society for Africanist Archaeologists met for the first time in Africa instead of Europe or the United States, joining forces with the Congress of the PanAfrican Archaeological Association (PANAF). The older generation beamed with pride. “Fifty years ago, many scholars thought that Africa was at best a trivial pursuit,” says archaeologist Merrick Posnansky of the University of California, Los Angeles. Now “African nationals are learning about their own past.”

    But the new generation is inheriting a troubled field. As Africa is rapidly transformed by development, archaeological sites are being destroyed faster than they can be studied. At the same time, there are “contrasting priorities between African nationals and foreign scholars,” says Posnansky. Rather than publishing papers, archaeologists who grew up on the impoverished continent are often motivated by the need to create jobs for locals and boost national or ethnic pride.

    “I joined archaeology as an activist,” says PANAF president Alinah Segobye, based at the University of Botswana in Gabarone. In the traditional view, archaeologists should be objective scientists who generate knowledge about the past and steer clear of politics. But for Segobye, “archaeology has been a tool to engage with development, focusing on such issues as the fight against poverty.” The notion that archaeologists can do their work “in a vacuum” is a myth, says Gerry Wait, director of Nexus Heritage in Fordingbridge, U.K., who gave a talk on the issue. “Archaeology is in the realm of political action.” Wait called on his colleagues to replace archaeology's ethical code of “do no harm” with the activist aim of “doing good.”

    Considering the audience, he was mostly preaching to the choir. But some voiced caution. “There can be tension between doing no harm and doing good,” says archaeologist Willem Willems of the University of Leiden in the Netherlands, especially when scientific evidence is ignored for the sake of political goals.

    Africa has such cases, says Arthur. In Zimbabwe in the 1990s, archaeologists helped the government reconstruct the 19th century capital of the precolonial kingdom near Bulawayo. The evidence showed that the main building had an east-facing entrance. But east-facing entrances are taboo to tribes that now live there, so “the house was reconstructed with the door facing the wrong way.”

    Such compromises may be a small price to pay to help Africans embrace archaeology, says Arthur. Nonetheless, he's uncomfortable wearing the “activist” mantle, preferring the more research-oriented “community archaeology” (Science, 26 August 2005, p. 1317). “When major sites are threatened, they still need digging and recording so that this information is not lost.” Whatever material his team can save will go into the country's first national museum.

  14. Preserving African Cultural Heritage

    Early Dates For Diepkloof

    1. John Bohannon
    Mystery.

    Are these stone tools (inset) from Diepkloof the oldest signs of modern culture?

    CREDIT: P-J TEXIER, DIEPKLOOF PROJECT (2)

    For the researchers who study the famed Diepkloof rock shelter in South Africa, the meeting was both a coming-out party and a defense. Diepkloof is a key Paleolithic site, the home of 60,000-year-old decorated ostrich shells that are among the first signs of symbolism. Now the team suggests that sophisticated behavior there stretches back as far as 130,000 years ago—nearly twice as old as at any other site.

    Guillaume Porraz of the University of Tübingen in Germany presented the first “grand synthesis” of 15 years of work at the site. On a screen behind him was a timeline of data, including an analysis of thousands of stone tools, plant and animal remains, and cooking hearths. In front of him, the international gathering of archaeologists collectively raised their eyebrows: He seemed to gain few immediate converts.

    The first signs of “modern” human behavior appear in southern Africa, in two bursts of innovative technologies. The first, called Stillbay, includes long, sharp blades that required complex planning to make (Science, 29 October, p. 659). Next came an even more sophisticated phase called Howieson's Poort, which includes the engraved ostrich eggs as well as highly standardized blades and points that were glued into spears, allowing long-range attack.

    Stillbay was a very brief period, possibly as short as a millennium, that ended about 71,000 years ago, according to previous work by a team led by Zenobia Jacobs of Australia's University of Wollongong (Science, 31 October 2008, p. 733). She used optically stimulated luminescence to date sediment from sites across southern Africa, including Diepkloof, and dated Howieson's Poort to between 65,000 and 60,000 years ago. Between the two periods, people reverted to simpler tools.

    The Diepkloof team found much older dates using thermal luminescence, which dates burnt stone instead of sediment. Those results, published last year, pushed the start of the Stillbay period back to 130,000 years ago and its end to 92,000 years ago. The team also says the Howieson's Poort period began 87,000 years ago and ended 55,000 years ago. Their new sediment analyses show that Jacobs's dates were based on erroneous assumptions, they say.

    Most archaeologists who spoke with Science were skeptical. If the new dates are right, says Michael Chazan of the University of Toronto in Canada, “it throws the [African] sequence out of whack.” But the jury is out until the Diepkloof team publishes its new analysis.

  15. Preserving African Cultural Heritage

    Latter-Day Livingstone Digs Along the Congo

    1. John Bohannon
    Odyssey.

    Livingstone Smith (squatting at right) digs for artifacts along the Congo River.

    CREDIT: KRIS PANNECOUCKE, © KMMA

    It was like a scene from Heart of Darkness, but with a happy ending and exciting scientific results. A wiry, bearded Belgian named Alexandre Livingstone Smith recounted his recent journey down the Congo River. Archaeologically, the sediment beneath the lush central African jungle is “unexplored territory,” says Livingstone Smith, an archaeologist at the Royal Museum for Central Africa (RMCA) in Tervuren, Belgium. To perform the first archaeological survey of the center of the continent, he hitched a ride with a team of biologists doing a biodiversity survey from April to June.

    Archaeologists have a detailed picture of human activity on each side of Africa, such as the early ironworking culture around Lake Victoria to the east and the complex pottery-producing societies of Cameroon to the west. Yet the connection between the two regions in the Congo River basin remains a blank spot. Parasitic diseases, inaccessibility, thick underbrush, and constant rain all make archaeological work in the rainforest difficult, but the main problem is the region's lawless violence. “When you excavate a long time at the same place, you become a target for well-planned attacks,” explains Livingstone Smith. Quick surveys of clearings along riverbanks are safest.

    So that's what the latter-day Livingstone did on his 500-kilometer journey. (Ironically, he may be a distant relative of David Livingstone, the legendary Scottish explorer who mapped the waterways of the former Belgian colony.) He joined the expedition at Kisangani, replacing his RMCA colleague Els Cornelissen on the boat, and traveled to Bumba, on a trip that was no leisure cruise. “The biologists would only stop for a day or two at any one place,” he says, “enough time to capture bugs and sample leaves.” For archaeology, that is a frenzied schedule, and meticulous excavation was out of the question. So Livingstone Smith surveyed rapidly, digging shallow test pits, and going deeper only at the most promising sites.

    The banks of the Congo were chockfull of archaeological material. Livingstone Smith and Cornelissen identified dozens of occupation sites containing everything from stone tools to pottery. They bagged samples of burnt charcoal and nuts to carbon-date back in the lab. The best site was an ancient burial tomb pointed out by a woman from a nearby village. “It was near the edge of a cliff and it turned out to be very deep,” he says. Inside were carefully arranged layers of pots, including one that seemed designed to hold a child's body. But like elsewhere, there were no traces of human remains. “The acidity of the soil dissolves all bone.”

    The design of some of the pottery—ranging from small cups to storage vessels with beveled rims and comb-pressed stamping patterns—is unlike any so far described. These could be a “missing link between east and west” Africa, says Livingstone Smith. Another style of pottery, called Imbonga and dated to roughly 3000 years ago, had been previously found in the region. But Livingstone Smith found Imbonga pots on a different river, 1000 kilometers east of their previously known location. That helps confirm the idea that people settled the region by river, he says.

    The results show that this kind of “broad-spectrum reconnaissance” is still valuable, says archaeologist Susan Pfeiffer of the University of Toronto in Canada. But a deeper understanding of the ancient people of the Congo River Basin will have to wait for government stability.

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