News this Week

Science  16 Oct 2009:
Vol. 326, Issue 5951, pp. 346
  1. Chemistry Nobel

    Honors to Researchers Who Probed Atomic Structure of Ribosomes

    1. Robert F. Service

    Just as architects usually get more glory than carpenters do, DNA is more famous than the molecular machine that converts genetic blueprints into proteins. But the ribosome was in the limelight last week with the announcement of this year's Nobel Prize in chemistry.

    The prize was awarded to three scientists who revealed the atomic structure and inner workings of the ribosome: Ada Yonath of the Weizmann Institute of Science in Rehovot, Israel; Thomas Steitz of Yale University; and Venkatraman Ramakrishnan of the Medical Research Council Laboratory of Molecular Biology in Cambridge, U.K. All three used a technique known as x-ray crystallography to pinpoint the position of thousands of atoms in the ribosome, and each will share one-third of the $1.4 million prize.

    “It's a fantastic accomplishment and one that everyone in the field has known for some time is worthy of such recognition,” says Wayne Hendrickson, an x-ray crystallographer at Columbia University. But Hendrickson and others—including all three new Nobelists themselves—note that the Nobel Committee's self-imposed rule limiting each prize to no more than three recipients left other ribosome pioneers out in the cold.

    Puzzle masters.

    Ramakrishnan (left), Steitz, Yonath, and others pieced together the ribosome's structure, which contains hundreds of thousands of atoms.

    CREDITS (LEFT TO RIGHT): MRC CAMBRIDGE; MICHAEL MARSLAND/YALE UNIVERSITY; WEIZMANN INSTITUTE OF SCIENCE

    “There were several scientists who contributed at least as much as the three of us,” Yonath says. Among those most often mentioned: Harry Noller of the University of California (UC), Santa Cruz, who, among other things, led the group that first solved the crystal structure of the complete ribosome; Peter Moore, a ribosome biochemist and Steitz's colleague at Yale; and Joachim Frank at Columbia, whose electron microscopy studies proved crucial in working out ribosomal structures. “It was an impossible situation to acknowledge them all,” says Jamie Cate, a structural biologist and ribosome expert at UC Berkeley.

    Ribosomes have sparked such scientific interest because they are the final major player in biology's central dogma, which describes how in all cells the genetic information in DNA is first translated into messenger RNA and then converted by ribosomes into proteins. To make that happen, dozens of different proteins and strands of RNA form a complicated machine divided into two principal components. The smaller component, known as the 30S subunit, works mainly to decode the genetic code in messenger RNA. The larger 50S subunit then takes this information and uses it to stitch together amino acids in the proper sequence to make up the final protein.

    Early researchers struggled to map the atomic structure of even one of these subunits. Producing an x-ray structure requires first creating crystals of millions of copies of a ribosome aligned in near-perfect order. Researchers then fire a beam of x-rays at the crystal. If the ordering of the crystal is precise enough, the pattern in which those x-rays deflect off the crystal can be used to map out the arrangement of atoms in the molecule.

    In 1980, Yonath created the first low-quality crystals of the 50S subunit. By 1990, she had upped the quality of her crystals, but she still struggled to map a good structure. Steitz and Moore jumped into the fray in 1995, following Yonath's recipe for making ribosomal crystals. In 1998, they used additional insights gleaned from electron microscopy studies to acquire a low-resolution 9-angstrom structure of the 50S submit. In August 2000, Steitz's group increased the resolution to 2.4 angstroms (Science, 11 August 2000, p. 905). Yonath's and Ramakrishnan's groups published slightly lower resolution structures of the smaller subunit the following month.

    Since then, the three groups and others have begun to combine these atomic snapshots, and others like them, into a jerky movie of the atomic dance ribosomes perform to translate genetic information into proteins. Structural biologists have captured dances of complex molecules before. The ribosome's dance, however, is more like a grand ballet, with dozens of ribosomal proteins and subunits pirouetting with every step while other key biomolecules leap in, carrying other dancers needed to complete the act.

    In a pair of research articles published online this week in Science (www.sciencemag.org/cgi/content/abstract/1179700 and 1179709), for example, Ramakrishnan and colleagues reveal in atomic detail the choreography of how two key cocatalysts—abbreviated EF-Tu and EF-G—swoop into the heart of the ribosome carrying amino acids, drop them off, and toss them to another site where they are tacked onto the end of the growing protein chain. Steitz calls Ramakrishnan's new work “very good” and confesses to some envy, as his own group toiled for years trying to achieve the same feat.

    Still, there are plenty of insights to come, Steitz and others say. So far, all known ribosomal crystal structures have come from prokaryotes. Researchers are racing to generate the first atomic-level structure of a eukaryotic ribosome, which are more complex and less uniform than those from prokaryotes. Yonath adds that her group is closing in on another long-standing goal: identifying what could be a “proto-ribosome,” a set of highly conserved RNAs within modern ribosomes that may have formed the original catalytic center for forging the peptide bonds that link amino acids together. If true, this proto-ribosome could add major support to the “RNA-world hypothesis,” which suggests that life originally evolved with its genetic blueprint encoded in RNA.

    The three groups have also begun to push practical applications of their work. All three, for example, have reported crystal structures that show how different antibiotics bind to the ribosome. Several companies are now using these structures in an effort to design new antibiotics against worrisome infections, such as methicillinresistant Staphylococcus aureus and tuberculosis. As these antibiotics and other advances continue to roll in, ribosomes figure to remain in the spotlight for many years to come.

  2. Economics Nobel

    Laureates Analyzed Economics Outside Markets

    1. Adrian Cho

    Last year, financial markets took the worst drubbing since the Great Depression, so perhaps not surprisingly this year's “Nobel Prize” in economics honors two researchers who studied economic behavior in other settings. Half of the 2009 Sveriges Riksbank Prize in Economic Sciences in Memory of Alfred Nobel goes to Elinor Ostrom, a political scientist at the University of Indiana, Bloomington, for her insights into the use of shared resources. The other half of the $1.4 million prize honors Oliver Williamson, an economist at the University of California, Berkeley, for his analysis of how a company decides what to do or make for itself and what to buy from others.

    “The really great thing is that this [year's prize] recognizes that we should look at the institutions that govern economic activity, which include a lot of things that aren't markets,” says Robert Gibbons, an economist at the Sloan School of Management at the Massachusetts Institute of Technology in Cambridge.

    Broader vision.

    Williamson (left) and Ostrom studied institutions other than markets.

    CREDIT (LEFT TO RIGHT): UNIVERSITY OF CALIFORNIA, BERKELEY; CHRIS MEYER/INDIANA UNIVERSITY

    Ostrom, 76 years old and the first woman to win the economics prize, has made her career studying how people cooperate to manage a common resource. For example, all users of a fishery can benefit by limiting their catches to prevent overfishing. But self-interest can torpedo cooperation, as each fisher can maximize profits by hauling in as much as possible. That “tragedy of the commons” seems to be an inevitable consequence of rational self-interest.

    Economists had consequently believed that cooperation had to be imposed by the government or induced by market incentives. And yet, beginning with fieldwork on efforts to halt saltwater intrusion into groundwater in southern California for her doctorate in 1965, Ostrom found that some communities do share communal resources. Through case studies, theoretical analysis, and experiments, she identified seven principles that foster cooperation. “Work on the commons is almost synonymous with Ostrom,” says Simon Gächter, an economist at the University of Nottingham, U.K. “She's a towering figure in the literature.”

    Ostrom found that individuals will cooperate if, among other things, they are able to participate in governance, monitor the compliance of others, and punish cheaters. “When people have trust that others are going to reciprocate, then there can be cooperation,” she says. “When there is no trust, there is no cooperation unless people are facing the gun.”

    Williamson, 77, studied how a company decides which goods and services to provide for itself and which ones it will buy—decisions that delimit the “boundary of the firm,” explains Gibbons. “At one time, Henry Ford was investing in rubber plantations in South America,” he says. “Now car companies buy tires.”

    Such decisions involve a balancing of benefits and costs. Suppose a sewing machine company uses a specialized part made by only one supplier. The company could save money by making the part itself, especially if the lone supplier inflates prices. On the other hand, if the company makes things that it could buy from one of several competing suppliers, it may waste money.

    Williamson's analysis serves both as a description of how companies naturally behave and as a prescription for how to organize a company, says Francine Lafontaine, an economist at the Ross School of Business at the University of Michigan, Ann Arbor. “I don't think there's an economist out there who doesn't know Williamson's name,” she says. “There's no question he deserves this recognition.”

    Nonmarket economics may also get more recognition, researchers predict. Close alliances between megabusinesses such as Wal-Mart and their suppliers are putting a new wrinkle on the boundary of the firm, Gibbons says. And Gächter says that climate change looms as the ultimate problem—and perhaps tragedy—of the commons.

  3. Neuroscience

    Enzyme Lets You Enjoy the Bubbly

    1. Greg Miller
    CREDIT: ISTOCKPHOTO.COM

    In 1988, a curious letter to the editor appeared in The American Journal of Medicine. One of the two co-authors, a physician named Stephen Kelleher, had recently climbed a mountain while taking the drug acetazolamide, commonly used as a prophylactic against altitude sickness. The climbing party had brought along a six-pack of beer, envisioning a celebratory drink at the summit. But the brew tasted flat, “like dishwater,” the letter lamented. Further experimentation “in the interest of science” revealed that acetazolamide also ruined the taste of carbonated soda but not whiskey. Noting that a previous study, published in Norwegian, had made similar observations, Kelleher and his co-author Mark Graber dubbed this effect the champagne blues.

    On page 443, a team headed by Charles Zuker, a neuroscientist now at Columbia University, helps explain this puzzling phenomenon. Using methods borrowed from electrophysiology and genetic engineering, the researchers identified a class of taste-receptor cells in the tongue that respond to carbon dioxide (CO2), the gas that gives sparkling beverages their fizz. They also report that the molecular sensor used by these cells to detect CO2 is an enzyme called carbonic anhydrase 4—one member of the class of enzymes inhibited by acetazolamide.

    “It's a genetic validation of the champagne blues,” says Stephen Roper, a neuroscientist at the University of Miami, Florida. Roper says the new work confirms and extends earlier evidence that carbonic anhydrases are responsible for CO2 perception, and it shows for the first time that the fizz-sensing cells on the tongue are the same taste-receptor cells that detect sourness.

    Historically, many researchers assumed that the tingling sensation of carbonated beverages arises because the bursting of CO2 bubbles stimulates mechanoreceptors in the mouth, says Zuker. But some observations, including those of the mountaineers, suggested that chemoreceptors on the tongue—such as those responsible for detecting sweet, salty, sour, bitter, and umami—also played a role, Zuker says.

    His team, which specializes in taste receptors, began tackling this bubbly debate by recording neural activity in the main nerve from the taste-receptor cells of the tongue in mice given a taste of club soda or exposed to CO2 gas. Both increased neural firing. Next, they repeated this experiment in mice genetically modified to ablate specific populations of taste-receptor cells. Mice that lacked sour-sensing taste cells exhibited no neural responses to carbonation, indicating that without these cells they didn't detect CO2.

    When the researchers then identified genes expressed only in the sour-sensing cells, one stood out. Called Car4, the gene encodes a carbonic anhydrase, which converts CO2 into bicarbonate ions and free protons. Applying a drug that inhibits carbonic anhydrases substantially reduced, but didn't totally eliminate, the mouse neural responses to CO2. The same was true in mice engineered to lack the Car4 gene. The team concludes that Car4, which sits in the membrane of sour-sensing cells, is the primary chemoreceptor for CO2. Zuker says the free protons created when Car4 breaks down CO2 probably stimulate the sour-sensing cells just as free protons from an acidic food or drink would.

    So why don't carbonated beverages always taste sour? Zuker isn't sure, but he speculates that the brain interprets input from the sour-sensing cells differently when it receives simultaneous input from the mechanoreceptive cells that respond to bursting CO2 bubbles. At the same time, he notes there is some evidence that carbonation can be perceived as sour: In German, for example, seltzer water can be called sauer Sprudel or Sauerwasser.

    Sadly, though, the work brings us no closer to a cure for the champagne blues. As Graber and Kelleher wrote more than 20 years ago, “Mountaineers must choose to leave either their acetazolamide, or their suds, at home.”

  4. ScienceNOW.org

    From Science's Online Daily News Site

    Physics Is All the Same to Birds and Babies Even with their tiny bird brains, rooks comprehend basic principles of physics at the same level as a 6-month-old baby—and beyond that of chimpanzees—a new study reports. But whether this understanding conveys any advantages remains an open question.

    Monkey Moms Have Madonna Moments It's a look that's been painted and photographed untold times: a mother gazing deep into her infant's eyes while the two smile and kiss. Now, scientists have discovered similarly intense shared gazing and facial expressions in monkeys. And that, the researchers say, means that this kind of maternal communication dates back at least 30 million years.

    CREDIT: IONICA CONSUEL

    Famous Royals Suffered From Hemophilia Many of Queen Victoria's male descendants died from a condition that caused them to bleed to death. This “royal disease” spread as Victoria's heirs married into royal families across Europe, decimating the thrones of Britain, Germany, Russia, and Spain. Now, new DNA analysis on the bones of the last Russian royal family, the Romanovs, indicates that the royal disease was a rare subtype of hemophilia known as hemophilia B.

    How We Lost Our Diversity If you compare any two people from far-flung corners of the globe, their genomes will be much more similar than those of any pair of chimpanzees, gorillas, or other apes from different populations. Evolutionary geneticists have now shown that our ancestors lost much of their genetic diversity in two dramatic bottlenecks that sharply squeezed down the population of modern humans as they moved out of Africa between 60,000 and 50,000 years ago.

    Read the full postings, comments, and more on sciencenow.sciencemag.org.

  5. Space Physics

    Tying Up the Solar System With a Ribbon of Charged Particles

    1. Richard A. Kerr

    Talk about rewriting the textbooks. Scientists thought they knew what the heliosphere looked like. The solar system's enveloping pocket filled with the solar wind's charged particles is plowing through the onrushing “galactic wind” of the interstellar medium in the shape of a comet, they all agreed. When NASA launched the Interstellar Boundary Explorer (IBEX) in October 2008, mission scientists expected it to confirm the textbooks.

    Instead, five papers published online in Science this week (www.sciencemag.org/cgi/content/abstract/1180906, 1180981, 1180927, 1180986, 1180971) report that IBEX revealed a sky-spanning “ribbon” of unexpectedly intense emissions of energetic neutral atoms (ENAs). No one knows what is creating the ENA ribbon, but everyone agrees that it means the textbook picture of the heliosphere is wrong. “I'm blown away completely,” says space physicist Neil Murphy of NASA's Jet Propulsion Laboratory in Pasadena, California. “It's amazing, it's opened up a new kind of astronomy.”

    The squeeze is on.

    A ribbon of energetic neutral atoms (reds to greens) mark where the galactic magnetic field compresses the heliosphere.

    CREDIT: ADAPTED FROM D. J. MCCOMAS ET AL./SCIENCE

    The meterwide, hexagonal IBEX monitors the edge of the solar system from Earth orbit by “seeing” the heliosphere's outer boundary in the “light” of energetic neutral hydrogen atoms. They're energetic because they are fast and neutral because they were once positive ions that lost their charge by picking up electrons. Those energetic parent ions lie near the heliopause, the boundary where solar wind meets galactic wind more than 100 times Earth's distance from the sun. Charged ions can't reach Earth, buffeted as they are by the solar wind and its embedded magnetic field. But once an energetic ion picks up an electron from a neutral atom, it can fly straight and true just like light. IBEX's two ENA detectors can then record the ENA glow from every direction.

    “The thing that's really shocking is this ribbon,” says IBEX principal investigator David McComas of Southwest Research Institute in San Antonio, Texas. Researchers had expected gusts in the solar wind blowing against the boundary to create 20% or 30% variations in ENA emissions, but the ribbon is 10 times that intense—a narrow band blazing across the sky like some Milky Way on fire. Charged particles have apparently become bunched along the ribbon near the boundary, says McComas, but how they got there “is still a big mystery.”

    Researchers do agree that the ribbon requires abandoning the textbook comet shape for the heliosphere. “We've learned from IBEX that [the comet shape] is not quite right,” says McComas. In the old view, the solar wind dominated the heliosphere, creating an ideal head while the tail swept downstream in the galactic wind. But when he and colleagues compare IBEX data with simulations, McComas says, they see signs that the magnetic field lines of the galactic wind impinge on the heliosphere, pushing it inward where the magnetic pressure is greatest. That also appears to be where the ENA ribbon forms. In the IBEX group's best model, the strong pressure from outside creates a misshapen but still recognizable heliosphere.

    Space physicist Stamatios Krimigis of The Johns Hopkins University Applied Physics Laboratory in Laurel, Maryland, sees a radically different picture. In another online paper (www.sciencemag.org/cgi/content/abstract/1181079), he and colleagues report that they found an ENA ribbon in observations made by the Cassini spacecraft orbiting Saturn, at somewhat different energies from those IBEX detects. But Krimigis thinks the external magnetic forces of the galactic wind dominate. “There is some sort of ‘head,’ but it's not the dominant effect,” he wrote in an e-mail, and there is “no ‘tail’ per se.” The heliosphere is more of a bubble, he says, squashed a bit by the galactic wind with solar wind escaping both upwind and downwind. “It looks more like a bubble of gas that wends its way through the galactic magnetic field,” he adds.

    Sorting out the heliosphere's true shape will take more time, says Murphy: “The geometry's tough.” The shape is no doubt somewhere between the two extremes of ideal comet and pure bubble, but all agree that researchers will have to understand how the ribbon forms to know the heliosphere's true shape. A key to that understanding, says Murphy, will be “how the fingerprint of the solar wind [is] seen to evolve” in the ENA observations as the sun moves toward the maximum of its 11-year cycle. Another key will be a lot more ribbon modeling.

  6. Virology

    In Holland, the Public Face of Flu Takes a Hit

    1. Martin Enserink

    AMSTERDAM—For the past 6 months, one could barely switch on the television here without seeing the face of famed virus hunter Albert Osterhaus talking about the swine flu pandemic. Or so it has seemed. Osterhaus, who runs an internationally renowned virus lab at Erasmus Medical Center in Rotterdam, has been Mr. Flu. But last week, his reputation took a nosedive after it was alleged that he had been stoking pandemic fears to promote his own business interests in vaccine development. As Science went to press, the Dutch House of Representatives had even slated an emergency debate about the matter.

    So far, few incriminating facts have emerged, and Osterhaus has the backing of his employer as well as Dutch Health Minister Ab Klink, to whom he is an adviser. Yet the media frenzy has cast a pall on Osterhaus's public image that may be difficult to undo, and some say it undermines the already flagging confidence in the safety of flu vaccines and the motives of those promoting them.

    Sidekick.

    Albert Osterhaus (right) is an adviser to Dutch Health Minister Ab Klink (left) and often joins him at news conferences on flu.

    CREDIT: ANP

    It's no secret that Osterhaus, a workaholic with more than 700 scientific papers to his name, also loves cameras and microphones (Science, 23 May 2003, p. 1228). But recently, some fellow scientists have accused Osterhaus of fear-mongering. Luc Bonneux, an epidemiologist at the Netherlands Interdisciplinary Demographic Institute, says Osterhaus is part of a “flu mafia” and that he's hyping the threats of both avian and swine flu. Miquel Ekkelenkamp, a microbiologist at University Medical Center Utrecht, called Osterhaus a “panic virologist” in a recent op-ed, adding that he “should be banned from television permanently.”

    The current firestorm erupted when reports surfaced that Osterhaus is co-founder of, and owns a 9.9% share in, ViroClinics, a Rotterdam spinoff from his lab that is involved in vaccine development. Fleur Agema, a member of the House of Representatives for the Party of Freedom, has said that's irreconcilable with Osterhaus's role on a Health Council panel that advises the Dutch government on flu vaccination.

    Osterhaus says ViroClinics isn't itself developing a vaccine against swine flu; it provides services—such as testing for antibodies in specimens—for a range of companies that do. His warnings about the pandemic peril don't affect ViroClinics' bottom line, says Osterhaus, because vaccine companies would have developed a vaccine against the new virus—and given his company business—no matter what. His company doesn't make more money if more vaccine is sold, he stresses.

    Erasmus Medical Center agrees, but the Health Council sees it slightly differently. Osterhaus is “a little too close” to industry to be a voting member on the panel, says Executive Director Anneke Wijbenga; to avoid even the appearance of a conflict of interest, he has the status of an “adviser.” Wijbenga stresses that there's nothing untoward about this situation, however, and that Osterhaus has been transparent about his financial interests. A Health Council statement also praises Osterhaus as “the absolute world top” in his field and says “we are glad … to make use of his expertise.” Health Minister Klink echoed that point of view in a letter to parliament. But Bonneux says that even as an adviser, “an alpha male like Osterhaus is going to dominate such a committee.”

    Bonneux has also taken aim at the European Scientific Working Group on Influenza (ESWI), an industry-supported group that Osterhaus has chaired since 2000. ESWI organizes meetings, promotes awareness about flu, and tries to raise vaccination levels. Bonneux says the group—which receives a €40,000 contribution from each of 10 companies annually—is little more than a lobby club that gives “trumped-up, sensational stories a scientific seal of approval.” ESWI spokesperson Derek Smith, a flu scientist at the University of Cambridge in the United Kingdom and a close collaborator of Osterhaus's, dismisses the claim, pointing out that ESWI's independence is guaranteed by a Code of Practice.

    Eelko Hak, a clinical epidemiologist at the University Medical Center Groningen who also sits on the Health Council panel, says that although the Dutch government encourages scientists to create spinoffs and ties with industry, popular opinion is still very uncomfortable with that idea. “It's typically Dutch to make such a fuss about this,” he says. Hak worries about the fallout from the affair; the Netherlands has always had very high vaccination rates, but a recent campaign against the human papillomavirus, which causes cervical cancer, flopped because of public distrust of health authorities. The Osterhaus brouhaha is another blow, says Hak.

  7. ScienceInsider

    From the Science Policy Blog

    French authorities last week charged a nuclear physicist working as a contractor at CERN with having ties to an Algerian terrorist organization. http://bit.ly/2cN84q

    Fifty-one academic biomedical scientists in Spain published an open letter in El País declaring their “confusion” at plans for a €5.3 billion science and innovation budget, a 0.2% increase over this year's budget. They are also worried that the government's new commitment to industrial research would reduce funding for grants. http://bit.ly/2eS1Lm

    Marcia McNutt and Arun Majumdar sailed through a Senate nomination hearing for positions as head, respectively, of the U.S. Geological Survey and the Energy Department's Advanced Research Projects Agency for Energy. http://bit.ly/3gzLmf

    The U.S. Centers for Disease Control and Prevention is urging people to get vaccinated against the H1N1 virus, which has killed 76 U.S. children. It also released results that suggested seasonal flu shots will not make people more susceptible to H1N1. http://bit.ly/4igbgM

    The U.S. patent office has dropped rules proposed by the Bush Administration to reduce paperwork by limiting the number of follow-on patent applications allowed for an invention. The patent bar, which had sued the agency over the proposal, declared victory, but reform advocates said that the proposed rules were a good idea. http://bit.ly/fE5Tw

    Congress has held up money to start building the $450 million National Bio and Agro-Defense Facility in Manhattan, Kansas, because of concerns about the safety of local residents. The money was left out of a bill funding the Department of Homeland Security as lawmakers asked to see results of further studies before providing any construction money. http://bit.ly/17WRud

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

  8. Newsmaker Interview

    Tonegawa Rethinks Japan's Premier Brain Research Center

    1. Dennis Normile
    Lab bench quarterback.

    As he shakes up BSI, Susumu Tonegawa will continue doing research at MIT.

    CREDIT: D. NORMILE/SCIENCE

    WAKO, JAPAN—Susumu Tonegawa, 70, has never shied away from challenges. He left Japan to earn a Ph.D. in molecular biology from the University of California, San Diego. After a postdoc at the Salk Institute for Biological Studies, also in San Diego, he joined the Basel Institute for Immunology in Switzerland, where he solved the riddle of how mammals produce billions of different antibodies needed to fend off infections—work that earned him the Nobel Prize in physiology or medicine in 1987.

    Tonegawa was then at the Massachusetts Institute of Technology (MIT) in Cambridge, where he shifted his focus to neuroscience and in 1994 became the founding director of what is now called the Picower Institute for Learning and Memory at MIT. After a 2006 flap over the aborted hiring of a young female scientist at another MIT institute, Tonegawa gave up the directorship to concentrate on research (Science, 24 November 2006, p. 1227). But this April, he became director of the RIKEN Brain Science Institute (BSI) in Wako, near Tokyo, a part-time arrangement that allows him to maintain a lab at MIT.

    BSI was established in 1997 and now has more than 50 principal investigators (PIs) and a $100 million annual budget. Considered Japan's flagship neuroscience institute, BSI is “pretty good,” Tonegawa says, but it doesn't match the reputation and productivity of top U.S. and European neuroscience centers. Tonegawa spoke with Science earlier this month about how he intends to raise BSI's game while coping with what he views as an inevitable downsizing.

    Q:What are your challenges at BSI?

    S.T.:Three major things. One is [rethinking the] direction of research. Second is [reforming] the system of principal investigator recruitment and promotion. And the third is to maintain good funding from the government and possibly other sources.

    Q:Do you intend to maintain BSI's broad research agenda or narrow the focus?

    S.T.:[Founding Director Masao] Ito felt he had to cover everything related to the brain: understanding the brain, protecting the brain, creating the brain, and nurturing the brain. It was very broad, … partially as a strategy for justifying this large amount of government funding. My view is that that's too broad. This institute is going to be run with my bias of what I think is important for the future. I would like to put more emphasis on understanding the brain. Also, BSI has been quite strong in disease studies. I want to continue to promote that.

    Also, we have to think about broadness versus concentrated research [because of] funding. In the early years, it was a tremendously rich institute. Now I don't think we can avoid some reduction [in the budget]. Gradually, the total number of labs will be reduced.

    Q:What are the most interesting questions in neuroscience right now?

    S.T.:The most interesting question is to try to understand circuits and the circuit basis of cognition. On one side, molecular and cellular studies have advanced tremendously. On the other side, there are very high-level studies in cognitive sciences, using [techniques such as] functional magnetic resonance imaging. The excitement for the coming decades will be to work out the events and processes that happen in between. We now have new technologies and enough knowledge to study the function of specific neural circuits that play a crucial role in behavior and cognition. And then you want to study which specific circuit goes wrong in neurodegenerative and psychiatric diseases.

    Q:BSI introduced a system of rigorous reviews of each PI every 5 years. Has that worked, and are you going to modify that approach?

    S.T.:I'm modifying it. A 5-year review repeated two times, three times, four times, I find, is silly. I'm introducing a tenure system. For the 22 or 23 people who have passed two reviews already, we've been requesting they get 15 or 16 letters from authorities throughout the world to decide whether they will be offered tenure. If they pass, they don't need to be reviewed anymore until they reach 65, when reviews will be reintroduced.

    I don't want scientists to occupy space and use up funding without being productive. In the U.S., it becomes more difficult to acquire grants. Here, with internal grants, I want to look at the person's productivity every 3 years and come up with a reasonable agreement to reduce space and funding. It is possible some people will continue to work at full scale; it will depend on the person. When we hire young PIs, we will give them 4 to 6 years to demonstrate that they are very viable scientists. If they don't get tenure, they have to leave within 2 years.

    Q:Can you do justice to this job splitting your time between here and MIT?

    S.T.:I cannot leave research; that's my driving force for being alive. My research is at MIT—I don't have a lab here. When I come here, I spend all of my time running the place. Many daily things I delegate [to four associate directors]. Of course, it would be better if [a director] was here all the time. But in that case, it would have to be somebody who can do this job with great enthusiasm and motivation without having a lab.

  9. Science Policy

    Russian Expats Challenge Government's ‘Disastrous’ Support for Science

    1. Andrey Allakhverdov*,
    2. Vladimir Pokrovsky*

    MOSCOW—On 2 October, 100 Russian researchers who permanently work abroad published a letter in the leading Moscow business newspaper Vedomosti complaining of “the disastrous situation in Russian basic research.” The letter, addressed to Russia's president and its prime minister, pointed in particular to extremely low levels of funding and a continuing massive brain drain. “We certainly hope to draw the attention of the political leadership of the country to the dangers of neglecting fundamental science and education,” says Andrei Starinets, a physicist at the University of Oxford in the United Kingdom and an author of the letter. “It takes years before investments in fundamental science and education pay off. These issues therefore require strategic rather than tactical thinking.”

    The letter hasn't drawn any formal response so far, but Russian officials last week boasted about their support of science, particularly a new program to lure back 100 expat researchers to work at least 2 months a year in a Russian research institute or university. “The process of return of researchers to Russia will become avalanche-like in the nearest future,” predicted the minister of science and education, Andrey Fursenko, at the Second International Nanotechnology Forum held in Moscow last week.

    Starinets and the other letter-signers suggested that the country try to attract world-scale scientific projects, using as a concrete example the construction of the International Linear Collider. This high-energy particle collider, envisioned as a possible successor to the Large Hadron Collider, would boost Russia's research in many fields, including information science, biology, and materials science, they say.

    Russian researchers within the country haven't all embraced the letter and its desire for big-science projects. Mikhail Gelfand, deputy director of the Kharkevich Institute for Information Transmission Problems, says that although more money for science would be good, “it would not give any result without radical reforms in science.” He also took issue with the suggestion to launch big projects, particularly to build a next-generation collider in Russia, suggesting that such projects would drain money from more worthwhile projects.

    Starinets notes that the letter was circulated for signatures only to scientists who have permanent positions abroad, to avoid any criticism that support was motivated by self-interest. He adds that colleagues inside Russia have not been silent: In September, hundreds of signatures were collected in an analogous appeal to the president by researchers inside the Russian Federation, including many prominent members of the Academy of Sciences.

    • * Andrey Allakhverdov and Vladimir Pokrovsky are writers in Moscow.

  10. Planetary Science

    Lunar Mission: A Slam, But Was It a Dunk?

    1. Richard A. Kerr

    NASA officials and scientists spent the better part of an hour at last week's press conference on the Lunar Crater Observation and Sensing Satellite (LCROSS) mission patting themselves on the back. The mission was a success, they said, all the while ignoring a very large elephant in the room: No one among the millions watching as a 2-ton hunk of metal slammed into the moon could see the much-ballyhooed spray of dust and debris that they had been told to look for.

    The impactor most certainly hit its target: the dark, frigid shadow inside Cabeus crater near the lunar south pole. And the nine instruments on the trailing LCROSS spacecraft returned all the planned data, which researchers will study for signs of water. But no visible flash was reported at the moment of impact, and no debris could be seen. “I'm not necessarily surprised,” said LCROSS principal investigator Anthony Colaprete of NASA's Ames Research Center in Mountain View, California. In exploration, “you just never know how these things are going to go. We just have to go back with a finer-tooth comb.”

    Actually, Colaprete had warned his colleagues, at least, about the possibility of a no-show debris plume. “It's a very unproven and highly unpredictable science, impact cratering,” he told an audience at the Lunar and Planetary Science Conference last March. Impact modelers working for the team had struggled to simulate the impact of a cylindrical—not a simpler spherical—object, and one that was hollow, not solid, like the LCROSS impactor. Plus, it smashed into a surface of unknown shape and composition. LCROSS was “the most challenging impact modeling I've ever done,” said Erik Asphaug of the University of California, Santa Cruz. There were just too many unknowns for him to be entirely comfortable with his results; impact on the odd unseen boulder, for example, could have sent most of the debris into the crater wall instead of into the sky.

    See anything?

    No dusty debris was seen after the impact, but hope remains for water vapor.

    CREDIT: PALOMAR OBSERVATORY/CALTECH

    LCROSS scientists may yet extract a debris plume from the data, but “the spectra is where the information is” about any water, Colaprete said, referring to spectral colors in the visible, infrared, and even ultraviolet returned by the trailing LCROSS spacecraft and by the Lunar Reconnaissance Orbiter. Some of these showed intriguing blips from the impact flash and the still-warm crater. There were also spectral changes above the impact site between pre- and post-impact. “What do these little blips mean? I don't know,” Colaprete said. “I'm just glad they're there. We're going to work on this feverishly.” Determining whether it was water will take weeks or months of data combing, and no public word about water will be forthcoming before the December meeting of the American Geophysical Union, he said.

  11. Science Education

    The Big Gamble in the Saudi Desert

    1. Jeffrey Mervis

    King Abdullah University of Science and Technology is betting that generous funding and great facilities will attract the talent it will need to become a top-ranked institution.

    Thirst for knowledge.

    A press conference during the inauguration of KAUST, which borders the Red Sea.

    CREDIT: AP IMAGES

    THUWAL, SAUDI ARABIA—The coral reefs that give the Red Sea its name provide a spectacular backdrop for the new King Abdullah University of Science and Technology (KAUST) here. The reefs also provide a unifying research theme for this lavishly endowed and precedent-shattering institution, which opened for business last month.

    Scientists at the university's Red Sea Science and Engineering Research Center plan to use the reefs as the centerpiece for efforts to understand all aspects of their marine environment, from the genomic to the ecosystem level. They'll also be probing the interaction of the land, air, and water that shapes the entire region. Eight other research centers have equally broad mandates—from desalination and the genetics of plant stress to renewable energy and clean combustion—and several more are in the offing. Together, the centers embody KAUST's credo: To pursue cutting-edge interdisciplinary science on issues of global importance in areas where Saudi Arabia has a compelling national interest and, possibly, a comparative advantage.

    Reporter's Notebook

    “We want people with big ideas and big ambitions. Timid individuals need not apply,” says KAUST's president, Choon Fong Shih. A world expert in computational fracture mechanics, Shih helped lift the National University of Singapore into the top echelon of research universities, and last year he came to KAUST to achieve the same goal.

    Thinking big is in the DNA of KAUST. The university's namesake, King Abdullah bin Abdulaziz Al-Saud, decided 3 years ago to set aside billions of dollars for an institution designed to help the country move from an oil-based to a knowledge economy (Science, 8 June 2007, p. 1409). The king chose Ali al-Naimi, the country's oil minister, to oversee his vision, and Saudi Aramco, the giant state-owned oil and petrochemicals company and the country's most visible symbol of internationalism, to manage the project.

    CREDIT: J. NEWFIELD/SCIENCE

    KAUST is perhaps the most-watched experiment in higher education taking place anywhere in the world. Its huge endowment is certainly an attention-getter: Two years ago, KAUST officials used a figure of $10 billion, although one knowledgeable source says the number is actually $20 billion. Saudi officials decided to make it a graduate-only university so that it wouldn't compete for undergraduates with existing Saudi institutions. KAUST hopes eventually to be the size of the California Institute of Technology—roughly 250 faculty and 2500 students—and to rival it in prestige. It's also the first Saudi institution of higher education to allow men and women to mix freely. But that policy has already been criticized sharply by conservative clerics from the country's dominant Wahhabi school of Islam and promises to be a source of continuing tension.

    Academic oasis

    The university sits on a 32-square-kilometer slab of desert an hour north of the port city of Jeddah, the jumping-off point for 4 million Muslim pilgrims headed to Mecca each year. Construction began barely 2 years ago, transforming this tiny fishing village into a teeming labor camp with as many as 30,000 workers. Last month, the 85-year-old monarch threw a party for some 3000 foreign dignitaries, visiting Nobelists, and the elite of Saudi society to showcase what his vast wealth has already created and, in a symposium on sustainability, to glimpse KAUST's future.

    Classes began on 5 September for the initial class of 400 students, most of whom have signed up for master's degree programs. The founding faculty members have been trickling in over the past few months. Although it will be months before most are able to move into their own labs, professors already have access to core facilities that are second to none among research institutions. KAUST has already assembled what may well be the most ethnically and geographically diverse group of academics anywhere (see graphic, p. 356). On one measure of diversity, however, KAUST has a long way to go: There are only five women among the founding faculty, and all are junior (assistant) professors.

    Royal donation.

    King Abdullah, shown at the inaugural ceremonies, is funding KAUST, his namesake university.

    CREDIT: SCOTT NELSON/KAUST

    None of the new recruits ever imagined doing science in Saudi Arabia until they heard what KAUST had to offer. “I loved, really loved, working at Woods Hole [Oceanographic Institution],” says Michael Berumen, a 29-year-old assistant professor of marine sciences and the first hire by the Red Sea center's director, James Luyten, a former director of WHOI. “But field-based work on reefs is such a huge part of what I do. And now I have the ability to just pop on a boat for a couple of hours, to grab some coral samples or check on the fish we've just been talking about. And then you add in these incredible facilities.”

    To retain the talent being amassed, Saudi officials know they will need to maintain a high quality of life. So within the barbed wire and concrete barricades that encircle the campus, Aramco is building an entire community, with all the residential, retail, recreational, and cultural amenities that any academic scientist would expect. The thousands of palm trees lining the main roads and academic complexes even help Berumen, an avid golfer, forget he's in a desert as he whacks balls at a driving range adjacent to a nine-hole golf course scheduled to open this month.

    KAUST may be a generation or more away from distinguishing itself academically, but its management structure already sets it apart from every other research university. The biggest difference is the absence of academic departments. Instead, faculty are grouped into three interdisciplinary divisions that will, at the outset, offer degrees in nine fields. “It's the way you'd want to do it if you could start a university from scratch,” says computational geophysicist Omar Ghattas of the University of Texas (UT), Austin, which has helped KAUST recruit faculty and create its program in the computational sciences and engineering. “The traditional role of a university was to train people in the canon of each discipline. But today's biggest problems—energy, climate change, nutrition, water conservation—are interdisciplinary.”

    For most scientists, however, the biggest difference is how their research will be funded. Rather than having to submit a never-ending stream of grant applications to government agencies and face depressingly low success rates, each faculty member has been given substantial internal support—$400,000 annually for assistant professors, $600,000 for associate professors, and $800,000 for full professors—from which they can hire students and technicians, buy materials and supplies, travel, and otherwise tend to the needs of their individual labs. The funding supplements full access to core lab facilities that include a 220-teraflops IBM Blue Gene/P supercomputer that will be upgraded to a petaflops machine, an industrial-quality nanofabrication facility, a state-of-the-art visualization center, and 10 nuclear magnetic resonance machines, including a 950-MHz instrument that is not yet on the market. “It was like setting a bunch of kids loose in the best toy shop in the world,” says Neil Alford, chair of the materials science department at Imperial College London (ICL), which helped KAUST assemble the noncomputing components of its core labs.

    CREDIT: COURTESY OF JIAN-KANG ZHU

    That's not all. Salaries are more than competitive with those in the West, say researchers, many of whom also receive free housing and other generous benefits. In fact, one prominent scientist wonders if the overall package may actually hinder KAUST's chances of producing great science. “I'm worried that they've gone beyond attracting people for the right reasons,” says Northwestern University chemist J. Fraser Stoddart, a 2007 winner of the (Saudi) King Faisal Prize for his pioneering work in molecular recognition and self-assembly relating to nanosystems. “Money doesn't buy everything. After living such a palatial existence, people may find it difficult to leave.”

    At the same time, KAUST scientists will be working without an academic safety net. Instead of a shot at tenure, professors receive 5-year contracts that can be extended indefinitely so long as they remain productive. Nobody Science spoke to feels it's much of a sacrifice, however. “Tenure isn't a major factor for me,” says Boon Ooi, a Malaysian-born professor of electrical engineering who had just been awarded tenure at Lehigh University in Bethlehem, Pennsylvania, when he decided this spring to come to KAUST to work on quantum nanostructures and their use as optical sensors. “I think it only slows down the pace of your research.” Ooi is certainly not afraid of change. His academic odyssey has taken him from Glasgow to Singapore to the United States, with a 3-year break to create, run, and then sell off a photonics company.

    Global outlook.

    KAUST's founding faculty and students come from around the world, but most are male.

    SOURCE: KAUST; CREDIT: MICHAEL ADOLPH/KAUST

    Even before Ooi and others arrived, they had begun recruiting the graduate students (meaning those already holding master's degrees) and postdocs needed to make their labs productive. KAUST effectively bought its initial group of students by paying for the students' last two undergraduate years in return for a nonbinding promise to apply to its master's programs. Most have kept their word.

    KAUST has also cozied up to the best academic programs and scientists in the world. One innovative approach, called the Academic Excellence Alliance, paid a handful of departments (including UT Austin in computational science and ICL in materials science) $25 million each over 5 years to identify and vet the best scientists in their field from around the world, many of whom wound up being hired. The alliance partners have also contributed curricula and begun research collaborations.

    Corporate culture

    Although Shih has promised that KAUST “will play by the rules” in terms of the free and open exchange of ideas and data, routine financial information about the university itself is hard to come by. Asked if a $3 billion figure in the local press for the cost of construction was accurate, Shih would say only that “we are grateful to Aramco for paying the full cost of developing, constructing, and outfitting KAUST's physical infrastructure and laboratories.” KAUST's operating budget, generated from the endowment and believed to be between $700 million and $1 billion, is also a secret, as is the size of the endowment itself. “I don't even know,” says Nadhmi Al-Nasr, interim executive vice president of administration and finance. But he adds that “we were not impacted by the economic downturn” because investment managers “didn't even decide to enter the market until the whole thing was over.”

    CREDIT: DAVID KEYES

    The dominant role of Aramco in the university's affairs also chafes. Aramco not only provides financial support, but many senior administrators, including Al-Nasr, are on loan from the company. Several faculty members complained to Science about certain corporate policies, from prescribed work hours to procurement practices, that they say are inappropriate for an academic setting. Some wonder whether Aramco's power over the university's purse strings will also give it undue influence in shaping academic policies.

    The sudden departure this spring of its founding provost, a prominent academic with deep roots in the region, reflects some underlying tensions within the top university leadership on managing that relationship. On 30 March, the KAUST faculty members were stunned to learn via an e-mail from Shih that Fawwaz Ulaby, a pioneer in radar remote sensing and a member of the U.S. National Academy of Engineering, was stepping down after only 1 year on the job. A charismatic promoter of the nascent university and an indefatigable traveler, Ulaby had recruited most of the faculty members. And his heritage—born in Syria, he was educated in Lebanon before coming to the United States for graduate study—was a source of great pride to Saudi officials.

    Rumors were rampant that Ulaby had suffered a heart attack during an intercontinental flight and that his heavy workload was ruining his health. Shih's short note said only that Ulaby had “considered the needs of his family” before deciding to step down, and Shih added last month that Ulaby's decision to leave “was entirely personal.” But Ulaby, now back at the University of Michigan, Ann Arbor, says the real reasons are entirely professional, not personal. “I categorically reject [the suggestion] that I stepped down for health reasons,” the 66-year-old electrical engineer tells Science. “I am as fit as can be.”

    Ulaby says he quit “because I was no longer allowed to do my job as provost.” That job included overseeing a seamless integration of the university's degree programs, research centers, and extensive core facilities. Instead, he says, the enormous challenge of building a graduate university from scratch and the imperative of opening on time led to “impossible disconnects” such as “hiring faculty and graduate students in chemistry when there is no degree program in chemistry. That happened, and it doesn't make any sense.” Ulaby says his attempts to “integrate those elements in an amicable fashion” were thwarted.

    Ulaby also worries that a corporate mentality is being applied to an academic setting. “KAUST has not created an environment in which faculty can enjoy a significant degree of freedom in carrying out their research,” he says, citing as one example the high-level, prior approval needed for travel to conferences and visits to other institutions. Ulaby says he still believes in the university's strategic goals—“to be small but spectacular in quality and scientific impact”—but that current policies may make them harder to achieve.

    Waiting to start

    The biggest complaint among faculty members is that they have been unable to start their research on campus. Although they are teaching classes, faculty members expect it to be another 6 to 12 months before they can move into their own labs. “This project is huge, and there are so many details,” says Kenneth Minneman, dean of chemical and life sciences and engineering and a former long-time professor of pharmacology at Emory University in Atlanta. “Somehow they lost sight of the fact that labs are an essential element of a research university. But the people at the top are now aware of the problems, and they know what needs to be done.”

    Mohamed Samaha, interim senior vice president for research and economic development, explains that getting the core facilities up and running was his first priority. “The next order of business is giving faculty the attention they need,” he says. Swing labs that will provide temporary space are scheduled to open as early as next month.

    CREDIT: COURTESY OF NIVEEN KHASHAB

    The delay is a minor impediment for computational scientists and engineers, says David Keyes, dean of mathematical and computer sciences and engineering. “We're internationally portable,” he quips. “But those who have to get into a system or develop a process are feeling the delays more acutely.” That would include Niveen Khashab, an assistant professor of chemical science who is using silica-based nanomachines to develop better drug-delivery systems. A former postdoc in Stoddart's lab, Khashab is coping by voluntarily teaching a second class this semester, twice the normal workload. In return, she's hoping next spring to work full-time in her lab.

    Khashab is one of only five women among the founding faculty. Shih says that's a concern and adds that he plans “to redouble our efforts to recruit women.” But he isn't sanguine about his chances of success. “There is a shortage of women everywhere, especially at the senior level, and we are competing with the rest of the world,” he says. About 20% of the students in the entering class are women, a percentage comparable to many U.S. graduate programs in the physical sciences and engineering.

    University officials hope that KAUST's presence will cause Saudi universities to raise their game. More grandly, Saudi officials talk about KAUST making the Middle East a major player in science and technology for the first time since the golden age of Islamic culture a millennium ago.

    Michel Bercovier, a prominent computational scientist at The Hebrew University of Jerusalem, thinks that could happen and says he's been impressed with the caliber of talent from his field that KAUST has already attracted. “KAUST is more than interesting, it's important. And politicians need to be aware of it,” he says. “I hope that KAUST will be a Sputnik moment for science in the Middle East.”

    Ironically, politics may also prevent Bercovier and other Israeli scientists from participating. Bercovier says he will measure KAUST's success by its ability to host top scientists from around the world for workshops and conferences. But because Saudi Arabia has no diplomatic ties with Israel, and the average Israeli citizen cannot obtain a visa to enter the country, his country's scientists won't be participating in KAUST-sponsored activities anytime soon.

    Given the kingdom's hard line on Israel and the large role of religion in Saudi society, Shih acknowledges that KAUST's ability to crack the top 20 list of research universities will depend in part on the Saudi government. “We are an academic institution, and we have to work within the laws of the country,” he says. “There are much larger issues here.”

  12. Neuroscience

    Fetal Cells Again?

    1. Constance Holden

    Despite past failures and growing skepticism about cell therapy in general, scientists once again plan to test fetal cell transplants on Parkinson's disease.

    In 1987, an American neurologist told The New York Times, “I think I witnessed history,” after watching Mexican surgeons perform a transplant of human adrenal gland cells into the brains of four people with Parkinson's disease. The physicians anticipated that the cells would turn into producers of the neurotransmitter dopamine, replacing the striatal neurons whose degeneration was clearly at the heart of the condition. At about the same time, Swedish doctors were experimenting with transplanting cells from fetal brains, a controversial strategy that produced such striking results in some cases that by 1997 about 200 patients around the world had received the treatment.

    But two fetal tissue trials in the United States in the 1990s that used sham surgeries as controls burst the balloon, indicating that any benefits may be little more than a placebo effect. Moreover, many of the patients developed “dyskinesias”—uncontrolled movements from excess dopamine from the brain grafts. It was a huge step backward; cell therapy for Parkinson's was all but abandoned.

    Taking the plunge.

    Surgeon Ivar Mendez readies a needle containing fetal brain cells.

    CREDIT: ROY DEMPSEY/DIVISION OF NEUROSURGERY, DALHOUSIE UNIVERSITY

    Then this decade, human embryonic stem (hES) cells came onto the scene, and scientists began trying to convert these malleable cells into dopamine-producing neurons that might provide a safer, more abundant and less controversial source of transplantable tissue than aborted fetuses. More recently, induced pluripotent stem (iPS) cells have been added to the mix. But as the lab research proceeds apace, there's growing doubt in some quarters about whether cell transplants will ever show a clear benefit for Parkinson's disease beyond what can be achieved by existing therapies. And researchers are increasingly realizing that there's much more to Parkinson's than a dopamine shortage.

    The debate about cell therapy for Parkinson's may soon become more intense as scientists in Europe, in collaboration with colleagues in North America, are in final negotiations for a large European Commission grant to conduct a new fetal cell transplant trial. The trial will refine clinical methods and be a “steppingstone” to therapies with cells derived from iPS or hES cells, says the principal investigator, neurologist Roger Barker of the University of Cambridge in the United Kingdom. Yet news of the plans dismays some. “I think it's a step backwards; … all the double-blind trials have failed,” says C. Warren Olanow, a neurologist at Mount Sinai School of Medicine in New York City, who headed one of those trials.

    Going head to head

    A half-dozen years ago, in the heat of political and scientific excitement over hES cells, Parkinson's disease was regarded as one of the prime candidates for stem cell therapy. But even as iPS cells have opened new vistas, the prospect of cell therapy trials has been steadily receding as scientists have gained new appreciation of both the difficulties of cell culture and the complexity of the disease itself.

    All over the world, researchers are trying to develop dopamine-producing cells from animal and human ES cells and from iPS cells. Although many have generated human dopamine-producing neurons in a dish, no one has proven that they have exactly the right kind: differentiated enough so the cells will not develop tumors but young enough to grow into the proper type of cell and make connections.

    So far, says Lorenz Studer of Memorial Sloan-Kettering Cancer Center in New York City, researchers have gotten things right with mouse cells. A big push now is testing human-derived cells in primates to find out what type is most likely to survive and build connections within the brain without forming tumors. For example, Evan Snyder of the Burnham Institute for Medical Research in San Diego, California, and colleagues are testing a half-dozen human cell types—including fetal brain cells, adult neural stem cells from cadavers, and ES and iPS cells at various stages of development—to see if they will engraft successfully in monkeys. “Nobody's ever compared them head to head,” says Snyder, who wants to ascertain the optimal stage of differentiation, the best place in the brain to insert cells, and whether the transplanted tissue needs to just churn out dopamine or reconstruct the whole striatal pathway, the neural circuitry that degenerates in Parkinson's.

    Studer points out that criteria have become very demanding for any such cell treatment: “To have a clinical trial, you have to have a treatment that promises to be better than anything now available.” Deep-brain stimulation, adopted in the 1990s, has raised the bar considerably: It can help patients when L-dopa medication loses its impact and can curb dyskinesias from long-term exposure to the drug (Science, 20 March, p. 1554). Studer predicts that in optimal circumstances—following noglitch studies treating Parkinsonian monkeys with human dopamine-producing cells—it would be at least 5 years before any clinical trial.

    Back to fetal tissue

    As these challenges have become clearer, some scientists have spent the past 3 years discussing a way to push the field ahead while human ES and iPS culture techniques are being perfected: a return to fetal tissue transplants. Despite the failure of the U.S. trials, which were funded by the National Institutes of Health (NIH), two uncontrolled trials held in Sweden in the 1990s appeared to produce striking improvements—with a handful of patients doing well up to 14 years later.

    These results have convinced some scientists that it's time to try again. If all goes as planned for the European Commission–sponsored trial, the first patients in a preliminary safety trial will receive injections of cells from the midbrains of 6-to-9-week-old fetuses in 2012. After that, a double-blind treatment trial—which Barker says would include sham surgeries “when we feel we have an optimal therapy for grafting”—will recruit patients at several centers in Europe and North America.

    Although Parkinson's disease researchers in Europe are generally enthusiastic about the plan, reaction among U.S. scientists is mixed. Ted Dawson, professor of neurodegenerative diseases at Johns Hopkins University in Baltimore, Maryland, finds it “surprising. … I had thought there was going to be a moratorium [on fetal tissue transplants] until we had a better understanding of dopamine neurons in transplantation.” Some scientists also point to long-term follow-up results reported last year in Nature Medicine, which revealed that the disease process had begun to affect a small portion of the fetal grafts in some patients.

    But psychiatrist D. Eugene Redmond of Yale University, who has done fetal tissue transplants in a monkey model of Parkinson's, points out that if you want to do a test of cell replacement, fetal brain tissue is currently “pretty much the gold standard.” Those prenatal dopamine neurons are at just the right stage of development and don't cause tumors, he explains. And they work better in monkeys (where scientists use a chemical to selectively kill off striatal dopamine cells) than do dopamine-producing cells grown from monkey ES cells, Redmond says.

    The European group insists that the new trials will be better controlled in every way than were those held in the 1990s. “We think the NIH trials were held at a time when several aspects of the technique were not fully developed,” says Anders Björklund, a fetal transplant pioneer at Lund University in Sweden. Barker says the team has identified some of the “critical factors” responsible for the failures. One is the mix of cells in the fetal tissues that were transplanted. Recent animal work in Björklund's lab has shown that if the fetal brain tissue contains a high proportion of dopamine neurons, they will offset possible dyskinesia-causing effects from other types of cells in the graft, principally serotonin neurons. To get the right mix, says Barker, there will be more “selective dissection” from the fetal brains (four to six are needed to treat each patient). Patients will also be younger (under 60), and with the aid of brain imaging, researchers will pick those whose dopamine loss is more restricted to the dorsal striatum.

    Neurosurgeon Ivar Mendez of Dalhousie University in Halifax, Canada, who has already reported success with implanting Parkinson's patients with fetal dopamine neurons, has worked out a standardized surgical procedure with the “Halifax injector,” a computer-controlled system for administering precise amounts of cells at specific brain locations through a hole in the skull. Mendez says about 4 million fetal brain cells—equivalent to about a drop of tissue—will be injected deep in each side of the brain. The placement of the graft deposits will cover as much of the dopamine-depleted striatum as possible, says Björklund.

    Old and new.

    Above: one of the first Swedish fetal cell transplant operations. Below: cell insertion points outlined by Mendez.

    CREDITS (TOP TO BOTTOM): STIG REHNCRONA; IVAR MENDEZ

    Neurologist Olle Lindvall of Lund University says the new trial will be able to address the “big question”: Why does the treatment bring “major recovery … in some patients and not in others”? Barker says that the answer may come from new information revealing subtypes of Parkinson's. Barker readily admits that cell therapy “is not a cure” but contends that it's an “open question” whether cell grafts are superior to deep-brain stimulation.

    Some U.S. observers agree that the trials are worth doing. “There's a lot of [unwarranted] bias in the field because of two [U.S.] clinical trials,” says Ole Isacson of Harvard Medical School in Boston. Redmond agrees: “A whole lot more is known about fetal tissue transplants than was known [in the 1990s]. It makes sense to continue looking.”

    The rest of the iceberg

    To others, the return of fetal cell therapy fails to give enough heed to recent advances in the understanding of Parkinson's disease. Stem cell treatment “looked most hopeful when people were treating [Parkinson's] just as a dopamine disease,” says Olanow. Degeneration of dopamine-producing cells is not the first or the only symptom of Parkinson's, however. It's become increasingly clear that, as neurologist J. William Langston of the Parkinson's Institute and Clinical Center in Sunnyvale, California, has put it, “Parkinsonism [that is, dopamine-related movement problems] is just the tip of the iceberg.” In reality, says Olanow, there is “very extensive pathology” that covers many neurotransmitter systems as well as the autonomic nervous system. Non-dopamine symptoms include bowel and bladder problems, attacks of low blood pressure, falling, “freezing,” sleep disorders, pain, depression, speech difficulties, and dementia.

    “If patients' only problems were related to dopamine deficiency, we would be able to maintain [them] for decades” with drugs and deep-brain stimulation, says neurologist J. Eric Ahlskog of the Mayo Clinic in Rochester, Minnesota. But given the extensive nature of the disease, any cell therapy “would need to be broadly administered and not just in one of a few brain regions.” It may be that cell transplants ultimately are most useful in furnishing trophic factors, protective chemicals that stave off deterioration of existing neurons—as some researchers hope will work in the case of amyotrophic lateral sclerosis.

    Olanow notes the limitations that pertain to dopamine-focused cell therapy also apply to current Parkinson's disease gene-therapy efforts, which center on introducing one or more genes involved in dopamine synthesis. Two groups, including one reporting in the 14 October online issue of Science Translational Medicine, have evidence that such gene therapy can restore dopamine production without associated dyskinesias in monkeys. This strategy has now moved into clinical testing. It's “exciting work,” says Olanow, but he contends that “the near-term future of cell and gene therapies based on dopamine restoration don't look particularly promising.”

    The Michael J. Fox Foundation for Parkinson's Research has also become much more cautious about the promise of cell therapy. The foundation is now placing its bets on new drug development and supports very little stem cell research. “I was totally naïve when I came to the foundation” in 2002, says CEO Katie Hood. “All my exposure was pop media; I thought it was all about stem cells.” Now, she says, “I have not totally lost hope on cell replacement,” but “I just don't think it's a near-term hope.”

  13. Newsmaker Interview: M. S. Swaminathan

    A Guru of the Green Revolution Reflects on Borlaug's Legacy

    1. Pallava Bagla

    Agricultural scientist Monkombu Sambasivan Swaminathan worked with Norman Borlaug for nearly half a century and spoke with Science about the Nobel laureate's contributions to South Asia.

    Comrade in arms.

    Borlaug (above) lives on in India through the genes of his Mexican wheat varieties, says Swaminathan.

    CREDITS: PALLAVA BAGLA

    NEW DELHI—During the Green Revolution of the 1960s and 1970s, Norman Borlaug's innovative semidwarf, rust-resistant wheat varieties, honed in Mexico, produced bumper crops—and saved countless lives (see p. 381). Average wheat yields in Punjab, for example, are 4.5 tons per hectare—more than five times higher than in pre-revolutionary times. Borlaug's standardbearer in India was agricultural scientist Monkombu Sambasivan Swaminathan, now a parliamentarian and chair of the M.S. Swaminathan Research Foundation in Chennai. Swaminathan, 84, worked with Borlaug for nearly half a century and spoke with Science about the Nobel laureate's contributions to South Asia.

    Q:What was Dr. Borlaug's impact in India?

    M.S.S.:Borlaug was the catalyst of change, a catalyst in the sense he brought these new varieties, these seeds of change.

    Q:Is there any estimate of how much of the wheat grown in India has signatures of the original material from Mexico?

    M.S.S.:Almost 100% [have at least] a few genes of the original material, particularly the dwarfing gene, and maybe there are a few genes for resistance to pests and diseases.

    Q:So Borlaug still lives and breathes in Indian farmers?

    M.S.S.:He lives through the genes.

    Q:Was Borlaug's contribution merely science, or did he go beyond science as well?

    M.S.S.:The Green Revolution was a synthesis of three elements: science, which is a prime mover of change, because we didn't have the new type of plant. Then public policy, and above all, farmers' enthusiasm. When we started the program, people discouraged us, saying farmers will not take your variety because it is short—lacking enough straw to feed livestock. We proved them all wrong, all those prophets of doom.

    Borlaug brought a revolution in ideas, a revolution in thinking, a revolution in technology. It's a totality. It was a great social change. It's quite likely that a billion people have been saved in India, Pakistan, and Bangladesh.

    Q:Did he worry that there are so many who are still malnourished and hungry?

    M.S.S.:He was a man of the field. He didn't like sitting in a room, in a laboratory; he was not very comfortable with seminars and symposia. He got impatient with ministers who are dining and wining and eternally talking poor and living rich.

    Q:But why are so many people still so malnourished?

    M.S.S.:Because of lack of money, lack of purchasing power. Indian famines are not famines of food anymore.

    I am happy in some respects. For example, our average life span has gone up enormously. What I am not happy about is that India still is home for the largest number of malnourished children, women, and men. I think it is inexcusable. It's very sad: A country which can make a nuclear submarine is allowing grains to be eaten by rats.

    Q:Did Borlaug reflect on this?

    M.S.S.:He was very perturbed by what is happening in India. As a humanist, he was deeply concerned, particularly about the issue of farmer suicides and why should it happen in a country like India—a democratic nation which ought to attend to the problems of its people.

  14. Profile: Veerabhadran Ramanathan

    From Burning Dung to Global Warming and Back Again

    1. Richard A. Kerr

    His childhood in rural India inspired the latest twist in climate scientist Veerabhadran Ramanathan's long career studying—and now fighting—climate change.

    Something in the air.

    This brown cloud—fueled by burning fuels in India—led Ramanathan to fly instrumented drones through polluted clouds.

    CREDIT: H. V. NGUYEN, C4/SIO/UCSD

    SAN DIEGO, CALIFORNIA—From his corner office on the terraced seaside campus of the Scripps Institution of Oceanography, Veerabhadran Ramanathan can look out 25 kilometers across the blue Pacific Ocean on a clear day. When San Diego's pollutant “brown cloud” blows in, the dim view reminds him of his current scientific bread and butter: the pernicious boost that such hazes give to global warming.

    More personally, the brown smudge on the horizon takes him back to his childhood summers in rural southern India half a century ago, where his grandmother would cough endlessly over her smoky indoor cooking fire of sticks and dung. Fires like hers still stoke the mother of all brown clouds, the one over South Asia.

    That connection helps explain Ramanathan's latest zigzag in a career full of unpredictable redirections. After discovering the unrecognized warming threat of trace greenhouse gases, provoking a reexamination of tropical meteorology, and revealing the insidious climate effects of brown clouds, the 64-year-old climate scientist is now going back to rural India. There he hopes to show how today's rural Indian women can cook more cleanly than his grandmother did while staving off disastrous global warming.

    Whether discovering a new global warming threat or testing a new cooking stove, Ramanathan “really is bold,” says Ralph Cicerone, president of the National Academy of Sciences and a 35-year colleague of Ramanathan's. “Though he's very mild-mannered, there's an internal drive that's pretty fierce.”

    Ticket to ride.

    Building an interferometer took Ramanathan to the United States.

    CREDIT: COURTESY OF VEERABHADRAN RAMANATHAN

    An aimless beginning

    That drive came late. From his years working on his bachelor's degree in engineering at the Annamalai University in Chidambaram, south India, Ramanathan says, “all I can remember is honing my skills in tennis and table tennis. I had this vision of being a tennis star.” Academically, “I had no goals for myself,” he recalls. He did bring a certain independence of mind to his studies. When Ramanathan—Ram for short—was 11, his father, a traveling salesman for Goodyear Tire and Rubber Company, moved the family from Madurai to Bangalore. School there was taught in English, not Ramanathan's native Tamil. While picking up English, “I lost the habit of listening to teachers” he couldn't understand, Ramanathan says. “I had to figure out everything on my own. It helped me enormously in research.”

    After graduating from the university in 1965, he took a job at a refrigerator manufacturing plant. “Two years into it, I hated it. My job was preventing the [refrigerant] chlorofluorocarbons from escaping; I was not successful.” He quit manufacturing and went back to school for a master's degree in engineering. There he got his first taste of research: building India's first Mach-Zehnder interferometer, an optical instrument for studying turbulent fluids. “I hadn't felt capable of anything like that,” he recalls. “That gave me confidence.”

    Off to the planets

    Research was not popular in India, however, and Ramanathan was reluctant to go back to manufacturing. “My dream was to come to America and drive American cars and enjoy the good life,” he says. So he wrote to fellow engineer Robert Cess of the State University of New York at Stony Brook (now Stony Brook University) asking about graduate work with the university's brand-new Mach-Zehnder interferometer. Cess took him on but “got bored with what I was doing” just as Ramanathan arrived, says Cess. He switched from studying combustion to studying the planets, taking Ramanathan with him. They applied an engineer's understanding of radiative transfer—the way heat is emitted, absorbed, and scattered—to the nature of the atmospheres of Venus and Mars and the way carbon dioxide traps radiation to produce a greenhouse. That was when “I realized I'd found my calling,” says Ramanathan, “working on the natural environment.”

    No climate jobs came up, but Ramanathan's radiative-transfer expertise won him a postdoctoral position in a NASA laboratory that applied radiative transfer to the problem of how spacecraft can blaze safely home through the atmosphere. Then his new boss, like Cess, switched fields, putting him to work on how ozone in the stratosphere influences surface climate.

    This latest random twist in the road carried Ramanathan into climate for good. At an ozone workshop, he learned of a recent landmark paper that tied chlorofluorocarbons (CFCs) to the chemical destruction of stratospheric ozone. Ramanathan recalled from his refrigerator days that CFCs would trap heat escaping from Earth and add to greenhouse warming. But were CFCs powerful enough greenhouse gases to compensate for their parts-per-trillion abundance in the atmosphere?

    Working nights, “I did the calculation six times,” he says, and every time the radiative transfer calculation showed that each CFC molecule was 10,000 times more effective as a greenhouse gas than was carbon dioxide. The result became the crux of his first single-author paper, a blockbuster in Science in 1975 that launched an entire subfield of climate research. Eventually, Ramanathan and others found that rising trace gases such as CFCs account for 45% of the drive behind greenhouse warming from gases.

    Against the tide

    Provocation comes naturally to Ramanathan, says his wife of 36 years, Giri Ramanathan. “What Ram is good at is being original,” she says. “He loves going against the tide, he loves to get people on his bandwagon.” After a stint at the National Center for Atmospheric Research in Boulder, Colorado, where he helped build NCAR's first world-class global climate model, Ramanathan moved on to the University of Chicago in Illinois. There he and his postdoc proposed a provocative hypothesis: Increasing clouds intervene to limit the greenhouse warming due to water vapor. In 1993, Ramanathan co-led his first major field study, the $20 million Central Equatorial Pacific Experiment (CEPEX), drawing on ship, plane, satellite, and balloon observations to test this “thermostat hypothesis.”

    Tropical meteorologists objected vociferously. “I didn't handle the controversy right,” says Ramanathan. At a meeting, “I pounded the table; I said something that made the community angry. I let personality come in the way.”

    Most researchers have since concluded Ramanathan—who has withdrawn from that field—was largely mistaken though perhaps ultimately constructive. “I think his [thermostat] paper is one of the most important in the meteorology of the tropics,” says tropical meteorologist Peter Webster of the Georgia Institute of Technology in Atlanta. “Not because it's right—I think it's a little wrong—but because it acted as a catalyst to get people thinking. It shows what a strong, ambitious scientist can bring about.”

    To the brown cloud's heart

    CEPEX may not have won the day for Ramanathan, but it did point him to the remainder of his life's work. CEPEX observations suggested to him that climate models were doing a lousy job of simulating the effect of aerosols, the microscopic particles of dust, sea salt, and pollutant crud that form a sun-dimming visible haze. To find out, Ramanathan co-led with Nobelist Paul Crutzen the $20 million Indian Ocean Experiment (INDOEX) in 1995 involving six aircraft and 200 international scientists.

    INDOEX was wildly successful, unfortunately. Researchers flew into an awe-inspiring brown cloud 3 kilometers thick spread over an area the size of the continental United States. It was so dense that it reduced sunlight reaching the surface by as much as 10% to 15%, an effect missing in the models. The problem was soot. The brown cloud's particles incorporated black carbon spewed by combustion—burning coal, diesel engines, and dung fires like the one Ramanathan's grandmother used to cook on. Black carbon–laden aerosols absorb sunlight and warm the air, boosting global warming. They may even be suppressing monsoon rainfall, depressing Indian agricultural production, and melting Himalayan glaciers, as Ramanathan has argued.

    Looking for a fix.

    Ramanathan is looking to clear the air with cleaner cook stoves in northern India.

    CREDIT: ADAM FERGUSON/VII MENTOR PROGRAM

    Getting personal

    INDOEX was a turning point. On the last INDOEX flight, into the Bay of Bengal off southern India, “I saw a vast cloud,” Ramanathan recalls. “I grew up in southern India. I thought, ‘I can't leave these millions of people to deal with this on their own.’ I knew this is where I was going to spend the rest of my scientific career.”

    That commitment evolved when Ramanathan turned 60 in 2004. Crossing that threshold “makes you look back,” he says. “I'd been working on [climate change] 35 years. All I had done was produce one bad-news paper after another. I had to do something good.” At about the same time, he was shaken by the new science about the brown cloud over Asia. He learned that “most of the black carbon is from biofuel burning,” he says. “That was it. It took me back to what I had seen in my childhood” watching his grandmother coughing over her cooking fire.

    Then, 3 years ago, he got yet another push. At the United Nations, “I gave a passionate speech” about global warming to an international group of high school students. “A shy African girl asked, ‘What are you personally doing about this problem?’ I had nothing to say.”

    On a personal level, he started taking the bus from home to Scripps and installed solarelectric panels on his house. More globally, he has launched Project Surya—Sanskrit for “sun.” Surya “was a gift from God … that I have a chance to go back and fix an age-old problem.” Surya is an experiment aimed at someday clearing a major part of South Asia's pall of brown clouds through cleaner ways of cooking. Ramanathan plans to put cleaner-burning cook stoves and solar stoves into the hands of those living in two rural areas of about 50,000 people each in the north of India and monitor the effects. Ramanathan expects to see dramatic declines in airborne black carbon both in their homes and in and near the villages.

    Fundraising has been slow so far. Ramanathan has put in $15,000 of his own money (he recently shared the $200,000 Tyler Prize for Environmental Achievement) and raised more from colleagues and foundations, although a large grant still eludes him. But there's no stopping, he says. “If you accept it's a problem, then you have to do something about it.” If the 4 billion people using biofuels “go the fossil fuels route, there is no hope.”

  15. News

    Alzheimer's Biomarker Initiative Hits Its Stride

    1. Greg Miller

    An effort to develop biomarkers for Alzheimer's disease is churning out new data and making plans to expand.

    Into the scanner.

    Researchers hope to use MRI brain scans to track the progression of Alzheimer's disease.

    CREDIT: © RANDY FARIS/CORBIS

    Imagine you're an executive at a pharmaceutical company and your scientists have just briefed you on a promising new drug for Alzheimer's disease. Dollar signs are no doubt swirling before your eyes. Alzheimer's afflicts 4 million people in the United States alone, and burgeoning elderly populations in countries like India and China portend skyrocketing demand for decades to come. But hold on. First, you have to run clinical trials. Because the cognitive tests and clinical measures used to gauge the efficacy of Alzheimer's treatments are notoriously variable, you may need to enroll 1000 people or more in the hope of seeing a statistically significant benefit. And given that Alzheimer's can be diagnosed definitively only by examining the brain after death, you can expect that at least 10% of the subjects won't have Alzheimer's but some other type of dementia that won't respond to your drug. Even those who do have Alzheimer's may be too far gone to benefit. Suddenly, those dollar signs begin fading from view.

    Such concerns are what motivated pharmaceutical companies to band together and join the National Institutes of Health to form an innovative partnership, the Alzheimer's Disease Neuroimaging Initiative (ADNI). Launched in October 2004 with $64 million to fund its first 5 years, its raison d'être is to develop methods for improving Alzheimer's disease clinical trials. ADNI has enrolled more than 800 volunteers between the ages of 55 and 90—roughly a quarter of them healthy, another quarter clinically diagnosed with probable Alzheimer's, and the rest diagnosed with mild cognitive impairment (MCI), a condition that often presages Alzheimer's. They undergo testing every 6 to 12 months with a variety of methods, including magnetic resonance imaging (MRI), positron emission tomography (PET) brain scans, and lumbar punctures to collect cerebrospinal fluid (CSF). The hope is to find biomarkers—signs of brain atrophy in an MRI scan, for example—that track the progression of Alzheimer's more faithfully than do the cognitive and clinical measures now used in treatment trials.

    Five years in, a trickle of data is becoming a torrent. ADNI researchers are now poring over brain scans and other biomarker data to document changes as people who started out with a clean slate of cognitive health have developed MCI, and as those with MCI have progressed to Alzheimer's. ADNI's organizers caution that it's too early to draw definitive conclusions, but some potentially useful lessons are emerging, including hints about which biomarkers best track different stages of the disease. Pharmaceutical companies are already incorporating some of the ADNI measures into clinical trials, and researchers in Europe, Asia, and Australia are developing similar initiatives (see box, p. 388).

    “As far as I can see, it's just been a phenomenal success,” says neurologist Michael Weiner of the University of California (UC), San Francisco, and the Veterans Administration Medical Center. Weiner, who is ADNI principal investigator, and the other project leaders found out last month that they'd won a $24 million Grand Opportunities grant from the National Institute on Aging that will enable them to expand the study to include people with even earlier stages of MCI. And Weiner says a proposal for ADNI2, a continuation of ADNI that would enroll hundreds more volunteers and expand the genetic testing arm of the study, will be sent off by the end of this month.

    Tracking a killer

    Although several drugs provide modest improvements in the memory impairments and other cognitive problems caused by Alzheimer's, so far no treatment has been proven to slow the underlying neurodegeneration (Science, 29 July 2005, p. 731). A handful of promising candidates have flopped in recent clinical trials, sparking much discussion about whether the field's longstanding leading hypothesis—that the accumulation of the β-amyloid peptide and formation of amyloid plaques is the core mechanism of Alzheimer's disease—is in need of revision, or worse.

    Yet many researchers contend that the recent trials are less a death knell for the amyloid hypothesis than an illustration of the need for better biomarkers. For one thing, they point out, the trials all enrolled people who already had a clinical diagnosis of Alzheimer's disease. For these patients, who presumably have significant neurodegeneration, clearing β-amyloid from the brain may simply be too little too late. The real test for the amyloid hypothesis will come from identifying people earlier in the course of the disease and giving them anti-amyloid treatments to see if it delays or prevents dementia. “It's now quietly recognized that Alzheimer's disease pathology is probably present 10 or 20 years before someone becomes demented,” says Weiner.

    Not a pretty picture.

    Amyloid deposits make for a colorful PIB scan of an Alzheimer's patient's brain (far right). People with MCI show diverse results.

    CREDIT: W. E. KLUNK AND C. A. MATHIS, UNIVERSITY OF PITTSBURGH

    Although the original goal of ADNI was to streamline clinical trials by developing biomarkers that track the progression of the disease more reliably than conventional clinical and neuropsychological measures do, Weiner says it's becoming apparent that some of the biomarkers under investigation may be valuable for diagnosing or even predicting Alzheimer's in patients suffering from only mild memory loss.

    The three types of biomarker measurements included in the original plans for ADNI—anatomical MRI scans, PET scans to measure metabolic activity, and CSF samples—were chosen because they'd already shown promise in mostly smaller, single-center studies. ADNI researchers developed extensive protocols so that data collected at the 59 centers could be combined and compared. Standardizing complex procedures such as MRI and PET scanning across multiple centers with different equipment wasn't easy, says neurologist William Jagust of UC Berkeley, who heads ADNI's PET core. “If you'd told me 10 years ago I'd be heading a multicenter imaging study, I'd have thought you were crazy,” he says. “The technology is just so complicated.”

    This is spinal tap.

    Cerebrospinal fluid may contain clues about one's risk for Alzheimer's disease.

    CREDIT: KAREN ORDERS PHOTOGRAPHY

    For the neuroimaging community, ADNI is also an unusual experiment in open-access science. All of the brain scans and other data procured so far are freely available to the scientific community at the ADNI Web site (www.loni.ucla.edu/ADNI/), typically within about a week of being collected, Weiner says. “Hundreds of scientists all over the world have made many tens of thousands of downloads,” he says. A significant number of the several dozen papers published so far on ADNI data have been authored by researchers not directly funded by the project, he notes. The open-access policy has given ADNI researchers an incentive to analyze and publish their data quickly, Weiner says. “It's really made me realize the power of releasing all the data.”

    A late addition

    Just as ADNI was getting under way in 2004, researchers at the University of Pittsburgh published the first report on a new method for detecting β-amyloid in the living human brain with a PET scan. The method uses a radioactive compound, called the Pittsburgh Compound-B (PIB), that binds to amyloid plaques. Researchers scrambled to secure funding to add on a PIB component to the original ADNI grant and test it in about 100 ADNI volunteers. In what came as a surprise to some researchers, nine of the 19 volunteers from the healthy control group tested “PIB+,” indicating significant β-amyloid deposits in the brain.

    Several larger studies that got under way before ADNI have found that about 30% to 35% of healthy people in their 70s and 80s are PIB+, says Chet Mathis, who was part of the team that developed PIB and now heads the β-amyloid imaging core of ADNI. (Mathis has a financial interest in PIB via a licensing agreement with GE Healthcare.) To some researchers, the PIB findings, along with earlier postmortem studies that reported amyloid plaques in the brains of elderly people who died without suffering dementia, are another strike against the amyloid hypothesis, Mathis says. But it's also possible that the healthy PIB+ individuals will eventually develop the disease, Mathis notes. He and others say following those individuals—in ADNI and other longitudinal studies—will be an important test of the amyloid hypothesis.

    Indeed, three non-ADNI studies published since 2008 suggest that PIB may be useful for identifying which MCI patients are most likely to progress to Alzheimer's, Mathis says. Pooled together, those three studies found that nearly 60% of PIB+ MCI patients advanced to Alzheimer's disease within a year or two, compared with less than 5% of the PIB-MCI patients. The ADNI data show a similar but less pronounced trend, Mathis says. All in all, he says, the findings so far suggest that PIB is “among the earliest biomarkers” for picking up signs of Alzheimer's.

    Compounds in spinal fluid may also indicate early signs of trouble, says Leslie Shaw of the University of Pennsylvania, who co-directs ADNI's CSF biomarker core. Previous studies found that the CSF of Alzheimer's patients contains low levels of β-amyloid (possibly because circulating levels of the peptide decrease as it becomes bound up in plaques) and high levels of tau, the protein that makes up the fibrillary tangles that are another pathological hallmark of the disease. In an April paper in the Annals of Neurology, Shaw and colleagues reported that the same pattern—low β-amyloid, high tau—was present in roughly 90% of CSF samples from ADNI volunteers who entered the study with MCI and progressed to Alzheimer's within the 1st year.

    A major theme emerging from the ADNI data is that different biomarkers may prove more useful for evaluating people at different points on the continuum from normal aging to mild cognitive impairment to Alzheimer's. Although CSF and PIB may be useful for predicting who is most likely to progress from MCI to Alzheimer's, other biomarkers may be more sensitive to changes at later states of the disease, says Clifford Jack Jr. of the Mayo Clinic in Rochester, Minnesota, who heads ADNI's MRI core. In a recent analysis, Jack and colleagues found that an MRI measurement of brain atrophy correlated well with cognitive changes over the course of a year. PIB measurements, on the other hand, changed little during this time span, the team reported in the May issue of Brain. In that study, Jack and colleagues used a “boundary shift integral” technique developed by Nick Fox of University College London to track changes in the fluid-filled ventricles in the brain, which expand as brain tissue degenerates. This algorithm is just one of many ways to quantify changes in MRI scans, and Jack notes that other ADNI researchers have demonstrated similarly promising results with other methods (see MRI image, p. 389).

    The other major neuroimaging component of ADNI, fluorodeoxyglucose (FDG) PET scanning, also tracks cognitive changes, says Jagust. Unlike MRI, which produces images of brain anatomy, FDG-PET uses radioactively tagged glucose to measure brain metabolism. In people with Alzheimer's, FDG-PET reveals reduced metabolism in the brain, particularly in regions of the parietal and temporal lobes, Jagust says. “FDG-PET is probably going to turn out to be a pretty good predictor in the early-to-middle stages of the disease,” he says. One popular hypothesis is that the method will fill in the gap between β-amyloid biomarkers and MRI, picking up changes in brain metabolism that occur when β-amyloid deposition is under way but not yet advanced enough to cause structural damage that shows up on an MRI scan.

    Energy crisis.

    FDG-PET scans show reduced metabolic activity (warm colors) in the brains of people with Alzheimer's disease (far right).

    CREDIT:SUSAN LANDAU, AND WILLIAM JAGUST

    Methods on trial

    But will ADNI pay off for the pharma companies paying roughly a third of its budget? Their road to regulatory approval for Alzheimer's disease treatments is difficult because the only measures now accepted by the Food and Drug Administration (FDA) for evaluating treatments are cognitive and clinical scales. But these measurements have their downsides, says Laurel Beckett of UC Davis, who leads ADNI's biostatistics core. “The cognitive measures are just so noisy,” Beckett says. “They go up and down for who knows what reasons because people just have good days and bad days.” That variability, coupled with the slow progression of the disease and the relatively modest effects of most candidate treatments, is why Alzheimer's trials have had to enroll so many patients in hopes of demonstrating a statistically significant effect.

    Some researchers hope it will one day be possible to use surrogate markers in clinical trials for Alzheimer's therapies, much as measurements of blood pressure and cholesterol levels have been used to approve drugs for heart disease. Several analyses of the ADNI data have suggested that some biomarkers, such as changes in brain volume measured by MRI, could reduce the number of patients needed by an order of magnitude. However, any Alzheimer's disease biomarker must not only track the progression of the disease accurately but also respond to treatment in a way that mirrors actual clinical improvements, says Russell Katz, the director of the division of neuropharmacological drug products for FDA. It's an exciting possibility, Katz says, but “we're nowhere near there.”

    Predicting trouble.

    A high percentage of ADNI-MCI subjects who progressed to Alzheimer's disease had abnormal CSF levels of various versions of tau (top left) and β-amyloid (bottom left), two biomolecules thought to play a role in Alzheimer's pathology.

    CREDIT: IMAGES COURTESY OF JOHN TROJANOWSKI

    Even so, companies are already incorporating ADNI-vetted biomarkers. “Every company that's working in AD [Alzheimer's disease] drug development is designing trials based on ADNI data right now, not as the only tool but as a significant tool,” says neurologist Paul Aisen of UC San Diego, who co-chair's ADNI's clinical core and oversees government-sponsored clinical trials as director of the Alzheimer's Disease Cooperative Study.

    At least one company is already using CSF biomarkers to screen subjects for a clinical trial, and others are considering it, says Aisen. Including only those people who show both β-amyloid aberrations and memory problems may help weed out misdiagnosed Alzheimer's cases and provide a better test of the proposed therapy.

    Some companies anticipate biomarkers will help establish that their treatments strike at the roots of the disease. Eli Lilly, which has two compounds in phase III trials for Alzheimer's, is using several biomarkers—including MRI, FDG-PET, and β-amyloid CSF and PET—in hope of demonstrating that these treatments provide biological as well as clinical benefits. “Our studies are set up so that they look quite a bit like ADNI,” says Eric Siemers, the medical director of Lilly's Alzheimer's team.

    Atrophy analysis.

    Paul Thompson and colleagues at the University of California, Los Angeles, have developed a tensor-based morphometry technique to measure brain atrophy in the brains of MCI and Alzheimer's patients.

    CREDIT: CHART CREATED FROM DATA PROVIDED BY LESLIE SHAW, XUE HUA, ARTHUR TOGA, AND PAUL THOMPSON/UCLA

    Such evidence won't directly influence the decision to approve the drug. But demonstrating a positive change in a biomarker—in addition to establishing a clinical benefit—might earn a company the right to claim its drug slows the decline of Alzheimer's disease, something no drug currently on the market can claim. Says Katz: “You can imagine the marketing advantage to the first company that gets a drug whose label says it's approved to slow the progression of Alzheimer's disease.”

    Different trajectories

    The 2-year followup data for ADNI subjects has just come in, and Beckett says she's been “going mad trying to compile the data and bring some order out of the chaos.” She says what's most striking about the analysis so far is that although the individuals in the normal, MCI, and Alzheimer's groups were intentionally chosen to be homogenous in their clinical profiles, within each group there is considerable diversity in the baseline biomarker profiles of different individuals and in the changes that have occurred during the first 2 years of the study. And that diversity has predictive value, Beckett says. “We are definitely seeing subtle changes in biomarkers that foreshadow both the cognitive outcomes and brain changes.”

    And the data will continue to roll in. Plans for ADNI2 include a greatly expanded β-amyloid–imaging arm. Because PIB is based on the short-lived Carbon-11 isotope, it has to be made on site, which limited its use to the 14 ADNI centers with their own cyclotron. If approved, ADNI2 will use a newer PET ligand based on Fluorine-18, which has a longer half-life, allowing it to be shipped to centers that can't make it themselves.

    ADNI2 would also include a beefed up genetics component, which, like PIB, was a late add-on to the first ADNI study. Researchers published the first work from this effort, a genome-wide association study in ADNI subjects, in August in PLoS ONE, reporting several genetic variations linked to hippocampal atrophy in Alzheimer's patients. Several more studies are nearing publication and many more are just waiting to be done, says the head of ADNI's genetics core, Andrew Saykin of Indiana University in Bloomington. “Investigators around the world are going to be chewing on this very rich data for a very long time.”

  16. News

    Longitudinal Alzheimer's Studies Go Global

    1. Greg Miller

    In the past few years, several international projects inspired in varying degrees by the Alzheimer's Disease Neuroimaging Initiative (see main text) have gotten off the ground.

    In the past few years, several international projects inspired in varying degrees by ADNI (see main text) have gotten off the ground. In Japan, neurologist Takeshi Iwatsubo of the University of Tokyo leads a national Alzheimer's neuroimaging study very similar to ADNI. In China, where the population over 60 is expected to triple by 2050, three large-scale longitudinal studies are under way; each plans to enroll at least 3000 people, says Maria Carrillo, who helps coordinate global Alzheimer's studies as senior director of medical and scientific relations for the Alzheimer's Association. Plans for a Europe-wide ADNI-like effort appear to have fizzled for political and logistical reasons, but several counties have their own projects, many of which have adopted ADNI methods, says Giovanni Frisoni of Fatebenefratelli Hospital in Brescia, Italy.

    CREDIT: SUZANNE BAKER

    The Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing (AIBL) will examine the role of lifestyle factors such as diet and exercise in cognitive aging, in addition to investigating blood biomarkers, FDG-PET, MRI, and PIB. The study is not modeled on ADNI, but researchers have adopted some of its methods so that all the neuroimaging data will be compatible, says AIBL Director David Ames of the University of Melbourne.

  17. News

    Massively Parallel Brain Imaging

    1. Greg Miller

    Mark Schnitzer is building tools to visualize neural activity in the fruit fly brain—100 flies at a time.

    Inventing technology that pushes the frontiers of brain research is the passion of applied physicist and neuroscientist Mark Schnitzer. His lab at Stanford University in Palo Alto, California, has cranked out several cutting-edge devices in recent years, including a 1.1-gram fluorescence microscope that can be mounted on a freely moving mouse to monitor the activity of neurons and glial cells and a 2.9-gram fiber-optic two-photon microscope for imaging cells deep inside the brain of an active rodent.

    Now he's working on an even bolder project, developing optical imaging technology for simultaneously recording neural activity in the brains of 100 fruit flies (Drosophila melanogaster), thanks to a $1.3 million grant from the Keck Foundation and a $2.5 million Director's Pioneer Award from the National Institutes of Health. Compared with current methods, which allow imaging only one fly at a time, such “massively parallel brain imaging” could open up research questions that have been out of reach, Schnitzer says. His comments have been edited for brevity.

    Q:What was the impetus for this project?

    M.S.:The basic idea was that neuroscientists have been starved for data, particularly brain-imaging data in awake, behaving animals. With invertebrates, and in particular with genetic model species like Drosophila, there's an opportunity to achieve a greater level of throughput and automation and at the same time to look at activity in populations of individual neurons as an animal executes a behavior.

    Q:How do you hope to accomplish that?

    M.S.:It's very early days, but our goal is to be able to examine 100 fruit flies in parallel. [The brains of individual] fruit flies have been examined previously by two-photon imaging with genetically encoded sensors for intracellular calcium, which is often used as an indicator of excitation in neurons. One of the limiting steps in this is the need to manually dissect the cuticle of the fly to access the brain optically. The first part of achieving higher throughput is to automate this step, so we're developing computer-directed laser microdissection. The basic idea would be to have a tray of flies, each fixed in place, and have the laser do the cutting automatically.

    With two-photon fluorescence microscopy, one can record in real time the calcium dynamics of neurons that have been genetically labeled with a calcium indicator. With a grid of laser beams, you could do that with an array of flies and collect multiple streams of data, each coming from the brain of an individual animal.

    A brainy idea.

    Mark Schnitzer wants to develop high-throughput methods for optical imaging in fruit flies (shown here in an early prototype).

    CREDITS (TOP TO BOTTOM): JUERGEN C. JUNG

    Q:Given that the flies have to be fixed in place, won't that limit the range of possible experiments?

    M.S.:Flies can exhibit motor behavior while fixed in place by walking on a stationary ball that rotates under their feet. That paradigm has been used for decades and was a point of inspiration for us. They can also respond to both odors and visual stimuli.

    Q:Is the goal here just to collect data more quickly?

    M.S.:Speed is certainly important. But I think if it really is possible to look at 100 flies in parallel, it will open up questions that can't be addressed today because the experiments are simply too prohibitive. One class of experiment would be to examine many flies of the same genetic strain and try to understand any differences in brain function, to look for elements of individuality among animals with the same genome. A complementary type of experiment would be to look at many flies that each have a somewhat different genetic makeup and try to understand how these flies behave and process information differently.

    Q:Do you envision this as something an individual lab would have, or would it be a shared resource?

    M.S.:It depends on a number of things, including how successful the technology is and how much it costs. If it turns out to be a large, pricey device, or if it's used in combination with other methods, that might justify a centralized location. For example, other groups are working on techniques for mapping all of the connections in neural circuits and on ways to automate tissue processing and histology. Some of these tools might get packaged together. One might first examine a large number of flies when they're alive and then subsequently look at them as histological specimens.

    Q:Going forward, how do you think such methods might change the way neuroscience is done?

    M.S.:High-throughput experimentation allows you to be much more systematic. I think we'll see a trend towards trying out all, or at least a large number, of the logical possibilities, as opposed to testing one hypothesis at a time. And I think as large data sets develop, the field will necessarily become more collaborative. It will require specialist skills in data mining and statistical and computational tools. We're already seeing a lot of that.

    Q:What motivates you to build microscopes?

    M.S.:The challenge of being able to watch the underlying cellular components that give rise to behavior, the challenge of seeing macroscopic phenomenon come to life out of microscopic components.

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