News this Week

Science  14 Jul 2006:
Vol. 313, Issue 5784, pp. 154
  1. CANCER RESEARCH

    Fake Data, but Could the Idea Still Be Right?

    1. Jennifer Couzin

    European investigators last week confirmed that a pioneering oral cancer researcher in Norway had fabricated much of his work. The news left experts in his field with a pressing question: What should they believe now? Suppose his findings, which precisely identified people at high risk of the deadly disease, were accurate even though data were faked?

    At least three groups—in the United Kingdom, the Netherlands, and Canada—are trying to determine whether oncologist Jon Sudbø of the University of Oslo's Norwegian Radium Hospital unwittingly hit on a way to identify those at high risk of oral cancer. A U.S. clinical trial, originally based on Sudbø's findings and since redesigned, could also offer some guidance.

    Sudbø has acknowledged that he invented some data, and a five-person investigative panel led by Anders Ekbom of the Karolinska Institute in Stockholm last week issued a report saying the bulk of his work was invalid (Science, 7 July, p. 29). “A fairly gross fraud has been perpetrated here, but it's still worth following up,” says Edward Odell, an oral pathologist at King's College London in the U.K. That's especially true, he says, because “the survival rate for oral carcinoma is very, very dependent on early diagnosis,” making prevention especially critical.

    Forecasting cancer.

    A panel headed by Anders Ekbom (inset) found that work on abnormalities predicting oral cancer (above) were faked, but the field wonders whether it can salvage the concept.

    CREDITS (LEFT TO RIGHT): SCIENCE PHOTO LIBRARY; CORNELIUS POPPE/SCANPIX/AP PHOTO

    Sudbø's work electrified the oral cancer community when it first appeared. In 2001 and 2004, he reported in The New England Journal of Medicine that individuals with mouth lesions that were aneuploid, containing an abnormal number of chromosomes, had an extraordinarily high risk of oral cancer, about 84%. He also claimed that this cohort was more likely to develop an aggressive form of the disease.

    Sudbø's reports were highly plausible. Cancer specialists had previously found that many oral tumors are aneuploid, and they also knew that mouth lesions with less dramatic genetic abnormalities are more likely to turn cancerous. Aneuploidy “might be an invaluable marker” for identifying people at high risk of oral cancer, says Ruud Brakenhoff, a cancer geneticist at VU University Medical Center in Amsterdam, but “we do not know” this any more.

    Brakenhoff and his colleagues quickly set about trying to replicate Sudbø's work. The Dutch group is studying tissue from mouth lesions collected from 150 to 200 people and assessing whether those with aneuploid lesions were more likely to develop cancer than the others.

    Odell's group, meanwhile, is examining tissue from about 150 people collected between 1990 and 1999 at his London hospital. “There is something in this,” he says, although he believes that aneuploidy is a less effective predictor than Sudbø claimed. Still, says Odell, in his hands it's at least twice as good as one current predictive approach, which grades the severity of cellular abnormalities visible under a microscope, such as enlarged nuclei or the crowding of cells. Odell presented some of his findings last month at an oral pathology conference in Australia, and both he and Brakenhoff hope to submit their work for publication this fall.

    “It's the start of stuff that needs to be done,” says Richard Jordan, an oral pathologist at the University of California, San Francisco. Like others, he believes that the best way to prove or disprove the aneuploidy theory is with a trial that follows patients prospectively rather than relying on stored tissue. That's what Miriam Rosin of the British Columbia Cancer Agency in Vancouver, Canada, is pursuing, with 200 individuals with various types of lesions; Odell says he's also planning such a trial.

    Meanwhile, a cancer prevention trial based on Sudbø's work has been overhauled in light of the misconduct. A multimillion-dollar trial funded in part by the U.S. National Cancer Institute (NCI) in Bethesda, Maryland, was poised to launch when the fraud came to light. The trial originally aimed to enroll individuals with aneuploid lesions and test the power of two drugs to prevent oral cancer.

    Now, says Eva Szabo, chief of NCI's lung and upper aerodigestive cancer research group, the trial will enroll 150 people with another kind of mouth lesion called loss of heterozygosity. These lesions include deletion of parts of chromosomes. (Aneuploidy involves the loss of whole chromosomes.) Volunteers will receive either the cancer drug Tarceva or a placebo, and a subset with aneuploid lesions as well as loss of heterozygosity may provide clues about how aneuploidy's risks stack up, Szabo says. The trial will be led by Scott Lippman of the M. D. Anderson Cancer Center in Houston, Texas, a Sudbø collaborator who was cleared of any misconduct.

    Oral cancer specialists originally wowed by Sudbø's research hope that the aneuploidy issue will be sorted out. “I think the question's going to be answered in the next 2 to 3 years,” says Jay Boyle, a head and neck surgeon at Memorial Sloan-Kettering Cancer Center in New York City, who collaborated with Sudbø and visited him in Oslo. Like many others, Boyle recalls his excitement when he first heard of Sudbø's findings. They offered “the possibility … [of treating] the more worrisome lesions more aggressively,” he says. Physicians like him still hope for some truth from the theory, although it may be less potent than the invented data suggested.

  2. STEM CELLS

    Team Claims Success With Cow-Mouse Nuclear Transfer

    1. Gretchen Vogel

    TORONTO, CANADA—The idea of creating an interspecies embryo makes some people squirm. But for scientists who hope to make genetically tailored embryonic stem (ES) cells, enlisting animal oocytes to reprogram human cells offers a possible alternative to using human oocytes, which are in short supply (see sidebar). And because such embryos would be unable to develop past the earliest stages, most researchers say there's nothing to be queasy about.

    At a meeting* here last month, a South Korean team claimed a rare success with so-called interspecies somatic cell nuclear transfer (iSCNT). Chang-Kyu Lee of Seoul National University reported that he and his colleagues used bovine oocytes to reprogram mouse somatic cells and then derived a mouse stem cell line from the cloned embryo. Other researchers said the work is intriguing but remain skeptical until it is repeated.

    Dozens of groups around the world have attempted iSCNT, and several live animals have been born after the DNA of an endangered species was transferred into an oocyte of a closely related domestic animal. But attempts to use oocytes of more distantly related species have largely failed. In 1998, the Worcester, Massachusetts-based biotech company Advanced Cell Technology (ACT) announced that it had used bovine oocytes to reprogram human somatic cells and develop a human ES cell line, but the company said it had discarded the cells without characterizing them (Science, 20 November 1998, p. 1390). And in 2003, Hui Zhen Sheng of Shanghai Second Medical University and her colleagues reported in the Chinese journal Cell Research that they had made ES cells by inserting human cells into rabbit oocytes. No other lab has successfully repeated either experiment.

    Alternative source.

    Bovine oocytes may be able to reprogram cells from other species.

    CREDIT: CHANG-KYU LEE

    As Lee described in Toronto, his team removed the DNA from cow eggs, injected a whole mouse somatic cell, and then used chemicals to kick-start embryonic development. The process was far from efficient, but Lee reported in a poster that his team managed to produce three blastocysts and a single ES cell line. The cells seemed to behave like normal mouse ES cells, forming various tissue types in the culture dish. When the team combined the cells with intact mouse embryos, they produced chimeric mice with two-colored fur. Lee says that since the poster was written, he and his colleagues have produced two more ES cell lines using the technique.

    Not everyone is convinced. Jose Cibelli of Michigan State University in East Lansing, formerly a member of the ACT team that attempted the cow-human nuclear transfer, says his lab at Michigan State spent 3 years attempting iSCNT without success. “This could be a huge breakthrough, but it's going to be scrutinized heavily,” he says.

    One reason for the doubts is that many scientists expect that a chimera created through iSCNT would receive most of its mitochondria from the oocyte, which would be incompatible with the nuclear DNA of the cloned cell. Mitochondria, the cell's power factories, carry their own DNA and are inherited from the mother through the oocyte cytoplasm. But Lee reported that in his experiments the problem seemed to solve itself. The freshly derived ES cells contained mitochondria from both the cow oocyte and the mouse somatic cell. But as the cells grew in culture, the mouse mitochondria became more prevalent, and the bovine mitochondrial DNA seemed to disappear.

    Lee says some species combinations may work better than others in iSCNT. His team had no luck trying to use mouse somatic cells and pig oocytes, he says, and bovine-human iSCNT is unlikely to work the same way as his bovine-mouse experiments. Until more studies are done, Cibelli says, Lee and other scientists with iSCNT claims “would have to do more than peer review” to convince their colleagues, perhaps allowing a separate lab to confirm the results.

    • * International Society for Stem Cell Research Annual Meeting, 29 June-1 July.

  3. STEM CELLS

    Ethical Oocytes: Available for a Price

    1. Gretchen Vogel

    TORONTO, CANADA—Obtaining human oocytes for embryonic stem (ES) cell experiments raises tricky ethical issues. Researchers want to be sure the donation is voluntary and that women are well-informed of the risks—two areas in which now-discredited stem cell researcher Woo Suk Hwang was faulted. At a recent meeting here, Ann Kiessling, director of the Bedford Stem Cell Research Foundation in Somerville, Massachusetts, described her group's successful efforts to recruit donors. Despite a rigorous screening process that eliminated more than 9 of 10 potential donors, the team had no shortage of oocytes. “We ran out of funds before we ran out of donors,” she says. Nevertheless, her experience suggests that collecting hundreds of oocytes ethically and safely will be expensive and slow.

    The group, which collected oocytes for its own experiments and also for the company Advanced Cell Technology in Worcester, Massachusetts, first placed an ad in The Boston Globe in September 2000 that read, “Research team seeks women aged 21 to 35 with at least one child to donate eggs for stem cell research; compensation for time, travel and child care expenses.” The requirement that women already have one child does bar some potential donors, Kiessling says, but it greatly lowers certain risks. If a woman has had a successful pregnancy, she says, “you know she's fertile, you know how she manages the hormones, and you lower the chance that 10 years later she might have fertility problems” that might be traced back to the donation.

    The Globe ad did not prompt a single response, Kiessling says, but ads in smaller regional papers were more successful. The team stopped running ads in 2003 because word of mouth had become the most effective source of donors. By the end of 2005, 391 women had inquired about the program; after a 12-step screening process, 28 started hormone injections, and 23 completed the process. Eight of those 23 donated twice; three donated three times. The donations yielded 274 oocytes, at an average cost of $3673 per egg. Factoring in the psychological and physical evaluations and the medical expenses, Kiessling says, the cost per woman of each completed donation cycle is $27,200.

    Very little of that money went to the donors. Women were reimbursed between $560 and $4004, depending on how many steps they completed. Although fertility clinics routinely compensate women for egg donation, some ethicists are wary of any payments that might encourage women to donate for money. Kiessling says donor programs need to have rigorous safeguards to prevent possible exploitation of donors, “but not paying isn't the answer.” More crucial, she says, is keeping the medical team separate from the research team and developing a rigorous screening program that ensures women are making well-informed decisions. Kathy Hudson of the Johns Hopkins University Genetics and Public Policy Center in Washington, D.C., agrees. Healthy volunteers are routinely paid for their participation in research projects, she says; “it seems just and fair that [oocyte donors] also be fairly compensated.”

  4. EVOLUTION

    Competition Drives Big Beaks Out of Business

    1. Elizabeth Pennisi

    When the new kid on the bus is bigger than you are, it might be time to give up your seat. That's what's happened to a small seed-eating bird in the Galápagos Islands. The medium ground finch used to have one island pretty much to itself—and free rein to eat whatever size seeds suited it most.

    Then a competitor, the large ground finch, moved in. And when the going got tough—a drought decimated seed supplies—this intruder's presence led to a change in the diet of the medium ground finches, as almost only those eating small seeds survived, Peter and B. Rosemary Grant, a husband-and-wife team from Princeton University, report on page 224. In about a year, the resident finch population retooled: Their beaks shrank, becoming better equipped for this new diet.

    This competitor-driven shift in beak size is an example of what evolutionary biologists call character displacement. Researchers have found apparent examples of displacement in natural settings and studied the process in laboratory experiments. But this is the first time they have seen it happen in real time in the wild, says Jonathan Losos, an animal ecologist at Harvard University: “This study will be an instant textbook classic.”

    Galápagos finches have fascinated biologists ever since Charles Darwin cataloged the great diversity of these birds' beaks. For the Grants, the finches have been their life's work. They have spent the past 33 years on one of the Galápagos' small volcanic islands, Daphne Major, recording the resident birds' births, deaths, eating habits, and so on, as well as weather and food-supply information.

    At the beginning of the study, the medium ground finch (Geospiza fortis) shared the island only with the cactus finch, which uses its pointed beak to eat cactus fruit and pollen. Lacking competition from other finches, the blunt-beaked medium ground finch depended on smallish seeds, which were easier to eat. That is, until a severe drought in 1977 devastated the plants that produced small seeds. For the most part, only those birds with beaks big enough to break open large, hard-to-crack seeds survived; in just a few generations, there was a 4% increase in average beak size (Science, 26 April 2002, p. 707).

    Beak push.

    For big seeds, the bill of the medium ground finch (bottom) was no match for that of the large ground finch (top).

    CREDIT: B. R. GRANT ET AL., SCIENCE

    In 1982, the large ground finch (G. magnirostris) settled on Daphne Major. At 30 grams, it was almost twice the size of the medium ground finch and easily cornered the market on a key food, Tribulus cistoides seeds.

    At first, the newcomers didn't pose much of a problem because food was plentiful. But by 2003, their numbers had swelled to about 350, and a drought that year set the stage for stiff food competition. In 2004, there were about 150 large ground finches and about 235 medium ground finches, and the birds soon exhausted the supply of large seeds. The death toll was severe: About 152 medium ground finches died, as did 137 large ground finches. Among the medium ground finches, the ones that had the largest bills were the worst off; only about 13% of them survived.

    Although the beaks of the island's large ground finch have not obviously changed since the drought, the medium ground finch seems to be returning to its smaller-beak days because of the selective pressure. Before the 2003 drought, medium ground finch males tended to have 11.2-millimeter-long bills, but by 2005, the bills averaged 10.6 millimeters, a 5% drop. The depth of the bill dropped from 9.4 millimeters to 8.6 millimeters on average, the Grants report.

    The change occurred with surprising rapidity, says David Pfennig, an evolutionary biologist at the University of North Carolina (UNC), Chapel Hill: “I expected [character displacement] to take much longer.” The Grants ruled out other possible causes of the change in beak size, such as the drought alone. After the 1977 drought, competition with another species was not a factor, and the beaks of the medium ground finches got bigger, not smaller. In this case, “you have the same drought, but selection is basically in the opposite direction,” points out Joel Kingsolver, an evolutionary ecologist also at UNC Chapel Hill. “For a nonexperimental study, [the setup] doesn't get any better.”

    Evolutionary biologists consider the paper important because it demonstrates the interplay between population numbers and environmental factors: The shift in beak size occurred only when there were enough large ground finches and large seeds were scarce enough to cause a problem, says Pfennig. “This study,” he adds, “will motivate researchers to go into the field and see if they can document other examples of character displacement in action.”

  5. PLANETARY SCIENCE

    Long-Term Mars Exploration Under Threat, Panel Warns

    1. Andrew Lawler

    While astronomers fret about the fate of the Hubble Space Telescope and earth scientists fear that NASA's budget woes will sink their current projects, their colleagues who study Mars are busy operating or planning an ambitious flotilla of rovers, orbiters, and robotic science labs. But their relative good fortune may be short-lived, a National Research Council (NRC) panel warned last week.*

    Calling Mars …

    The NRC panel wants to resurrect the Mars Telecommunications Orbiter and give it additional capabilities.

    CREDIT: JPL/NASA

    NASA currently spends $650 million a year on Mars exploration, and that figure was projected to double by 2010. But as a result of the demands of the space shuttle, President George W. Bush's human exploration initiative, and cost overruns among other science projects, Mars spending now is slated to remain flat through that period. The agency recently canceled a telecommunications orbiter, halted efforts to develop a Mars sample return, and proposed scaling back some smaller missions. “We're in pretty good shape in the near term,” says Reta Beebe, an astronomer at New Mexico State University in Las Cruces who chaired the 15-member NRC panel. “But the future is pretty nebulous, and the entire Mars program is under threat.”

    Beebe's panel recommended that NASA resurrect the telecommunications orbiter and add a science component to study the martian upper atmosphere as well. The agency in recent months has quietly been considering a Mars Science and Telecommunications Orbiter (MSTO) to do just that. The spacecraft, which could be launched as early as 2013, would gather scientific data and then drop into an orbit where it would relay data from the martian surface to Earth. The NRC committee also suggested that NASA consider building a seismic network in 2016 to ensure that researchers don't neglect Mars's structure and evolution in their quest to find past or present life, and that it delay by 2 years the 2016 launch of the Astrobiology Field Laboratory to allow time to take into account data from earlier missions.

    The panel sidestepped the question of where funding for the orbiter would come from. But Beebe warned that sticking with a flat budget would mean that “we may not be able to sustain what we've developed” during the past decade. And she added that scientists are willing to be realistic. Although committee members are upset that the sample-return mission is no longer on the books, they also recognize that the fiscal constraints mean such a multibillion-dollar effort likely won't happen in the coming decade.

    NASA's chief Mars exploration scientist, Michael Meyer, says the proposed cuts to future years forced the agency to push sample return and geophysical rovers into the unbudgeted future. But he's confident that building the MSTO is realistic and that international partnerships could make the other projects doable. But he warns that conducting both a 2016 mission and an astrobiology flight in 2018 might prove too costly.

    Reaction from outside researchers was mixed. “We need to get our act together, but we are hamstrung by our budget,” says Ray Arvidson, a planetary scientist at Washington University in St. Louis, Missouri. He praised the report as an important step in laying out a long-term plan. But Noel Hinners, a geochemist, former NASA manager, and now executive at Lockheed Martin Astronautics in Denver, Colorado, questions the need for a telecommunications orbiter. He adds that a sample return is still possible by 2016 or 2018 if NASA and Mars researchers made it a top priority.

  6. PALEONTOLOGY

    Vigorous Youth for Tyrannosaurs

    1. Erik Stokstad

    Childhood was the best time to be a tyrannosaur. So says the first study to chart the personal ups and downs of this famed group of predators. On page 213, a group led by Gregory Erickson of Florida State University in Tallahassee reports that juvenile tyrannosaurs enjoyed a survival rate unmatched by that of many modern vertebrates—humans excepted. Presumably, that was a perk of being the meanest kids on the block. But as soon as puberty hit, life got rough.

    The findings come from survivorship curves, a type of demographic analysis that reveals what proportion of a birth cohort manages to escape dying each year. Researchers have plotted many such curves for modern animals but none for dinosaurs, because they lacked large samples and a way to determine how old the animals were at death.

    The team looked at 22 individuals of a tyrannosaur called Albertosaurus sarcophagus from a Canadian site about 200 km northeast of Calgary. The skeletons probably washed up in riverbank deposits over weeks or months about 70 million years ago. To figure out the animals' ages at time of death, Erickson applied a relatively new technique (Science, 5 November 2004, p. 962), counting the annual growth lines preserved in the bones of their calves and feet. Because no hatchlings were found in the deposit, the team assumed that their mortality rate lay within the dismal range of 50% to 80% for modern vertebrates. A tender young tyrannosaur, they reasoned, would probably have been just as vulnerable as young birds or crocodiles to predation, starvation, or trampling.

    Juveniles fared much better. Between the ages of 2 and 13, the average mortality rate dropped to 3.5%. Erickson thinks the young dinosaurs' size protected them: Even a 2-year-old was bigger than any other predator alive at the time. “I can't imagine too much tangling with a 2-meter-long tyrannosaur,” Erickson says.

    Unlucky exception.

    Juvenile tyrannosaurs, like this Gorgosaurus, are rare in the fossil record because they tended to escape death.

    CREDIT: ED GERKEN/BHIGR

    But hazards mounted once Albertosaurus entered its teens. The death rate for 14- to 23-year-olds climbed to an average of 22.9%. The team thinks fresh dangers may have arrived with sexual maturity. Females would have undergone the stress of laying eggs, and males might have competed for mates.

    Old age was likely just as unpleasant. The deposit contained only one Albertosaurus as old as 28 years, evidence that few survived that long. The researchers found the same pattern of survivorship when they examined bones from three other tyrannosaurs: Tyrannosaurus, Gorgosaurus, and Daspletosaurus.

    Other paleontologists say survivorship curves could shed light on dinosaur ecology. “You could build up a whole ecosystem of dinosaur populations and see how they interacted,” says Matthew Carrano of the Smithsonian Institution's National Museum of Natural History in Washington, D.C. Adds Thomas Holtz of the University of Maryland, College Park, “There's a lot of potential here.”

  7. PLANETARY SCIENCE

    Peeling Back One More Layer of Asteroid Mystery

    1. Richard A. Kerr

    When NASA's NEAR Shoemaker mission reached the asteroid Eros 6 years ago, planetary scientists hoped it would settle a question that had vexed them for decades: Do ordinary chondrites, the most common meteorites that fall on Earth, come from big, roughly chondritelike bodies that make up most of the inner asteroid belt? Sadly, the orbiting craft's sensors left the question up in the air (Science, 14 December 2001, p. 2276). Now researchers say a closer look at the data shows that Eros could indeed be a source of chondrites—but skeptics say the case is still open.

    No match.

    Eros still isn't a perfect compositional fit with ordinary chondrite meteorites.

    CREDIT: EROS: JPL/NASA

    “This is about as sure as things get when the rocks are not sitting on your lab table,” says asteroid researcher Clark Chapman of the Southwest Research Institute in Boulder, Colorado. Other NEAR Shoemaker data, however, suggest there's more to Eros than ordinary chondrite.

    The problem started with sulfur. Data from NEAR Shoemaker's spectrometers confirmed that Eros has the right mix of minerals and elements to be one big, ordinary chondrite, with one exception: Sulfur was less than half as abundant as it should be.

    There were two possible scenarios. First, Eros is indeed an ordinary chondrite, but in its outermost few micrometers—the part sampled by x-ray spectrometry—more than half the sulfur has been vaporized by the solar wind or micrometeorites, so-called space weathering. The more dramatic possibility was that early in its history, Eros melted, and the molten rock carried much of its sulfur into its interior. In that case, rock from asteroids like Eros would now be very different from the asteroid's original composition—and thus could not have given rise to ordinary chondrites.

    Cosmochemists Nicole Foley and Larry R. Nittler of the Carnegie Institution of Washington's Department of Terrestrial Magnetism, meteoriticist and team member Timothy McCoy of the National Museum of Natural History in Washington, D.C., and others decided to test the two scenarios. They looked at trace elements—minor components of the asteroid's recipe. The elements chromium, manganese, and nickel are all less volatile than sulfur and thus should be impervious to space weathering, Nittler says. But, like sulfur, they would be “strongly affected by any differentiation.”

    The group painstakingly analyzed readings from NEAR Shoemaker's x-ray spectrometer and compared them with compositions of ordinary chondrite meteorites. The results showed that the three trace elements are as abundant on Eros as in chondrites, the group reports in Icarus this month. “They've really made the case that space weathering was responsible for the depletion,” says asteroid specialist Michael Gaffey of the University of North Dakota, Grand Forks.

    Made it, but not quite closed it, Gaffey adds. It's still possible that Eros melted slightly—enough to wipe out the original mineral structure without changing Eros's elemental composition. In that case, Eros and its asteroid cousins would still be ruled out as sources of ordinary chondrites. And team member Lucy McFadden of the University of Maryland, College Park, and colleagues report discrepancies in data from NEAR Shoemaker's mineral-identifying, near-infrared spectrometer. “There's more there than just ordinary chondrite components,” says McFadden, “but I don't know what it is.”

    “The only resolution is going to be getting a sample,” McFadden says. “Our hope is that something fell into Hayabusa,” the Japanese spacecraft that may or may not have collected a sample from the asteroid Itokawa (Science, 31 March, p. 1859) and may or may not make it back to Earth in 2010.

  8. MICROBIOLOGY

    Bacteria Help Grow Gold Nuggets From Dirt

    1. Richard A. Kerr

    It's not just in fairy tales that buried treasure appears as if by magic. Australian researchers report on page 233 that they've found soil bacteria that pull dissolved gold from their surroundings and deposit it on grains of gold where they live. The study provides “sound and convincing evidence” that microorganisms can play a role in growing gold nuggets, says geomicrobiologist James Fredrickson of Pacific Northwest National Laboratory in Richland, Washington. Such bacteria may even have had a hand in producing some of the great gold ore deposits—but don't start strip-mining the backyard just yet.

    Bugs at work.

    Nuggets that up close look like gold-encrusted bacteria (top) are covered by biofilm (blue) of gold-depositing bacteria.

    CREDITS: F. REITH ET AL., SCIENCE

    Researchers had long suspected that bacteria help create the flecks and nuggets of “secondary” gold that prospectors pan from streams and miners dig from certain long-buried gold deposits. At microscopic scales, secondary gold can strikingly resemble mounds of bacteria, as if microbes had encased themselves in the metal. And in the lab, some bacteria defend themselves against toxic dissolved gold by turning it into the metallic form. But connecting the dots between field and laboratory evidence was “dicey at best,” Fredrickson says.

    Geomicrobiologist Frank Reith of the Commonwealth Scientific and Industrial Research Organisation in Adelaide, Australia, and his colleagues set out to forge the link. At two Australian sites 3400 kilometers apart, they collected grains of secondary gold from soils that lie over rock whose gold leaches up into the soil. On the nearly pure gold grains, they found striking examples of “bacterioform” gold overlain by biofilms of bacteria and their exuded slime. Genetic analysis showed that the bacteria belonged to as many as 30 species, most of which could not be found in the surrounding soil. The most pervasive species was genetically nearly identical to the bacterium Ralstonia metallidurans, a microbe well-known for its ability to precipitate some heavy metals from solution in the lab. Reith and colleagues showed that R. metallidurans can also precipitate gold.

    “I'm not claiming all the gold grains are formed by microorganisms,” says Reith, but “there's certainly something going on. These organisms are active and creating gold.” Fredrickson agrees that Reith and his colleagues have “made a strong case for microbiogenic gold mineralization” but cautions that the work can't prove that microbes grow gold nuggets. As a next step toward that goal, Fredrickson says, researchers must pin down exactly how they do it.

  9. BIOMEDICINE

    Selling the Stem Cell Dream

    1. Martin Enserink

    Tomorrow's treatments today—that's the promise of a growing number of companies offering cell therapies untested in rigorous clinical trials. Some experts say the claims must be challenged

    A wide net.

    Many providers of cell therapy recruit patients through their Web sites.

    If you suffer from an incurable neurological disease such as multiple sclerosis (MS), Parkinson's, amyotrophic lateral sclerosis (ALS), or Huntington's disease, a clinic in the Netherlands says it may be able to help you. In a procedure that takes just a few hours and costs $23,000, the Preventive Medicine Center (PMC) in Rotterdam will inject stem cells obtained from umbilical cord blood into your bloodstream and under your skin.

    The clinic has treated more than 200 patients so far; the results are “often spectacular,” according to its Web site. Although PMC sees mostly neurological patients, it offers stem cell treatments for a wide variety of other diseases as well, including arthritis, lupus, Crohn's disease, heart disease, hernia, insomnia, sexual dysfunction, depression, and loss of memory, hair, or appetite.

    PMC is one of a growing and diverse group of companies and institutes around the globe offering patients stem cell therapies or related treatments that are viewed by mainstream researchers as unproven. Some clinics use umbilical cord blood, whereas others inject fetal cells or cells derived from patients' own bone marrow. Some carry out operations themselves, whereas others act as middlemen, providing cells and linking patients with doctors willing to inject them. Almost all have Web sites to advertise the promise of the new therapies, often with hopeful case reports. The sites help recruit patients with what regular medicine cannot provide: a hope of recovery.

    Although these clinics have already treated thousands of patients, a dozen stem cell scientists and physicians familiar with one or more of the treatments told Science they oppose them, often vehemently. Not only is there little or no evidence for the procedures' efficacy, the experts say; in many cases, there's also no published animal work to suggest they might work in humans. Most clinics appear to have no interest in rigorously collecting data about benefits and risks, critics say, and some may harm patients' health. Some companies are “preying on desperate patients,” says stem cell scientist Irving Weissman of Stanford University in Palo Alto, California. “It's a horrible disservice.”

    Most of the clinics have not revealed full details of their treatment protocols. A handful of researchers have attempted to get a foot in the door, however, hoping to glean information about risks and benefits of cell therapy by systematically studying patients before and after they embark on treatment. Patient organizations and research foundations are trying to find out more, too, although they say it can be impossible to get even basic facts about the treatments.

    The result, Weissman fears, may be that stem cell research—already under criticism for its use of embryos and suffering from the Korean cloning scandal—could see its reputation tarnished further. “I'm beginning to get pretty angry about this,” says stem cell researcher Christine Mummery of the Hubrecht Laboratory in Utrecht, the Netherlands. “I think as a scientific community we have to speak up,” adds Stephen Minger, director of King's College's Stem Cell Laboratory in London.

    Indeed, some scientists have asked regulatory authorities to intervene. After Dutch neurologists complained, for instance, the Dutch Health Inspectorate began looking into PMC and a second company in the Netherlands, Cells4Health.

    A quest for a cure

    John Franken of Landgraaf, the Netherlands, was a gymnastics champion before he broke his neck during a trampoline accident 18 years ago. Since then, Franken, 44, who has an administrative job at the Open University in Heerlen, has been unable to move without a wheelchair and unable to sit up for more than 6 hours a day. He follows spinal cord research closely on the Internet, and he started a foundation to promote the search for a cure in 1995. He got very interested in Huang Hongyun, a doctor in Beijing who injects patients suffering from spinal cord injuries or neurological diseases with cells from aborted fetuses. But when Franken contacted Huang for an appointment, he learned that he'd be on the waiting list for years.

    Then in May 2005, Franken read a message posted on a patient forum by Cornelis Kleinbloesem, director of Cells4Health, who said his company had helped a paraplegic patient get a treatment with her own bone marrow cells in a Turkish hospital. Four weeks later, she was able to walk again, as a Turkish magazine called Tempo had documented, Kleinbloesem wrote. A second patient had seen functional improvement as well; “these results are very promising,” Kleinbloesem's message concluded.

    After a series of medical tests, Franken was approved to undergo the same therapy. Friends and colleagues helped raise the $23,000 for medical fees and travel. In January, Franken flew to Baku, Azerbaijan; at a private clinic, neurosurgeon Elchin Jabrayilbayov made a 12-centimeter cut in his neck and upper back—the graphic pictures are on Franken's Web site—to inject the stem cells directly into the lesion.

    When he returned home, Franken started describing his experiences on his Web site. “I know my body is working on something,” he wrote after 3 weeks, “but I'm trying to be realistic.” He was told it might take at least 6 weeks before the cells had any effect—and so he waited.

    Franken's story is not unusual. Many patients hear about anecdotal evidence through the Internet, says John McCarty, a biologist hired last year by the ALS Treatment Development Foundation (ALSTDF) in Cambridge, Massachusetts, to investigate stem cell treatments and other new therapeutic options for ALS. Many spend upward of $20,000; some borrow to the limit or sell their homes, McCarty says.

    What they get differs from clinic to clinic (see table). Whereas PMC uses cells derived from cord blood, Cells4Health arranges for patients' own bone marrow cells to be transplanted directly at the site of the lesion to treat spinal cord injuries, vascular diseases, and damage from heart attacks and strokes. Huang, who works at the Beijing Xishan Institute for Neuroregeneration and Functional Recovery in Shijingshan District, says he uses so-called olfactory ensheathing glial (OEG) cells to treat neurological patients. In Kiev, Ukraine, a clinic called EmCell also uses various types of cells derived from fetuses to treat more than 50 different diseases, including many aging-related problems and HIV.

    Verifying the claims

    Amid all the hype about stem cells, it's easy to forget that very few cell-based therapies have proven their mettle in rigorous clinical trials. For some leukemias, doctors can obliterate a patient's own bone marrow and transplant cells from a donor—a well-established stem cell therapy. In the past few years, several studies have also shown that bone marrow cells can help repair the heart after a myocardial infarction (Science, 9 April 2004, p. 192), and others have suggested benefit for patients with a damaged cornea. “That's it, in terms of stem cell therapy,” says Minger.

    For the moment, most stem cell scientists say they are working on basic questions: how to make stem cells morph into exactly the cell type needed to treat a condition and how to ensure that they survive after being injected, are not rejected by the host's immune system, and don't start multiplying unchecked.

    Baku and back.

    John Franken traveled from the Netherlands to Azerbaijan to receive an injection of cells for his spinal cord injury.

    CREDIT: CHRIS KEULEN

    The cell clinics are forging ahead with treatments anyway. Take EmCell, which says it has experience in multiple diseases from treating more than 2000 patients in 13 years. ALSTDF decided to take a close look in 2004, after a story in a Wyoming newspaper reported that an ALS patient could walk again thanks to treatment by EmCell. According to a review on ALSTDF's Web site, the foundation's investigators talked to the doctor performing transplants and sent the company a detailed questionnaire. “EmCell didn't answer many of the questions, and in some areas refused to elaborate on important details such as their method for screening against the AIDS or hepatitis viruses,” the ALSTDF report says.

    But some of EmCell's procedures “clearly raise red flags,” the report goes on. For instance, the company injects cells into patients' abdomens; most doctors think it's “implausible” that they would travel to the brain and work against ALS, the ALSTDF investigators say. The inventor of EmCell's therapy, according to the company's Web site, is its president, Alexandr Smikodub, who also heads the Cell Therapy Clinic at Ukraine's National Medical University. He has published seven PubMedlisted papers, six in Russian and one in Slovak, the last in 2001. In response to questions from Science, Smikodub sent a fax detailing his professional history and EmCell's procedures and giving examples of successfully treated patients. Although he has made presentations at many scientific meetings, Smikodub wrote, the international scientific community has largely ignored him. He did not respond to ALSTDF's allegations.

    PMC Director Robert Trossel discussed his company's therapy but said details will be in a paper he plans to submit later this summer to Nature, Science, or The Lancet. “We're dying to let you know,” Trossel says. (If accepted, the paper would be his first in a PubMed-listed journal.) PMC specializes in alternative treatments such as herbal medicine and ozone therapy. But recently, Trossel says, his team has learned how to make stem cells home in on the place where they are needed by coinjecting bits of messenger RNA and using each tissue's “specific electromagnetic frequency.” (To avoid having the injected cells seek the wrong target, he also recommends that patients replace mercury-containing fillings first.)

    The unconventional cell therapy that's received the most scientific scrutiny so far has been Huang's. With his staff of about 70, Huang has treated more than 1000 patients. His therapy is based on a line of research pioneered by neurobiologist Geoffrey Raisman at University College London, who discovered 20 years ago that OEG cells, which reside in the nasal mucosa, guide olfactory nerve fibers into the brain during development. After culturing, Raisman and others have found, these cells can help repair rats' damaged spinal cords. (Patients often refer to them as “stem cells” on the Internet, but Huang says they're not; Raisman says “you could call them adult stem cells.”)

    View this table:

    Raisman and colleagues are planning a small clinical trial in which they will treat patients who have a specific nerve injury that paralyzes the arm with their own OEG cells. But he points out that Huang's treatment is different: It uses fetal cells, which have not been proven effective in published animal studies and which could cause rejection problems because they are not matched to the patients' tissue type. Raisman sees little scientific basis for Huang's treatment, which “saddens” him.

    Still, some scientists are intrigued by Huang's claims of success. In 2004, with Huang's consent, a group from the Miami Project to Cure Paralysis at the University of Miami in Florida sent two scientists, James Guest and Tie Qian, to Chaoyang Hospital in Beijing, where Huang then worked. The U.S. duo followed 12 patients from just before treatment until a few days after and took home a sample of therapeutic cells. In a report on the Miami Project Web site, the scientists say that they observed some “modest improvements” in the patients but also noted side effects, including meningitis. Earlier this year, Guest and Qian published an extensive report in Spinal Cord about one patient, an 18-year-old Japanese boy with spinal cord injury. They reported that he experienced “rapid partial recovery” after the procedure—even though a lab analysis cast doubt on the claim that the injected cells were OEG cells. The researchers suggested they might be another cell type and added that the injection may have contained other “neurotrophic” compounds.

    Others became interested. Bruce Dobkin, a spinal cord-injury specialist at the University of California, Los Angeles, recalls how he and others quizzed Huang at a dinner party during a 2004 meeting in Vancouver, Canada. Several scientists offered to do a more extensive follow-up of his patients, Dobkin says. Huang appeared “delighted,” and Dobkin, Guest, and Armin Curt of Balgrist University Hospital in Zürich, Switzerland, examined seven patients before they traveled to Huang's clinic and again up to 14 months after therapy.

    Their paper in Neurorehabilitation and Neural Repair 2 months ago delivered a harsh verdict. Five patients came home with side effects, the U.S. group reported, including three with meningitis, and none showed improvement. What's more, the report says, Huang's team doesn't appear to follow up on patients, nor does it systematically collect data about the treatment's efficacy and risks. “It shocked even us,” says Dobkin.

    In an e-mail to Science, Huang called Dobkin's paper “rubbish” and a “vicious attack” that he would not discuss. The Miami team did not find OEG cells in his sample, he says, because they used the wrong staining techniques. And Huang accuses Guest of “misconduct” for publishing the paper in Spinal Cord without his permission and without consent from the Japanese patient. Huang has filed complaints with the University of Miami's Institutional Review Board and the Office of Research Integrity (ORI) at the U.S. Department of Health and Human Services. ORI says it has no jurisdiction, but a university panel is investigating the allegations.

    Meanwhile, neuroscientist Wise Young of Rutgers University in Piscataway, New Jersey, where Huang worked from 1999 to 2000, has defended Huang. On CareCure, an Internet forum that Young administers, he wrote that Dobkin “evaluated seven patients out of several hundreds operated on by Dr. Huang … to make some far-reaching negative conclusions about the work.”

    Ideally, any unproven cell treatment that's tried on humans should be tested as part of a randomized, controlled clinical trial, most stem cell researchers say; patients should participate free of charge, be fully aware of the risks, and be carefully monitored. Few clinics or companies in the new cell-therapy market appear to have run trials on these lines.

    But one of them has tried—only to be rebuffed. Cells4Health set up a clinical trial last year in collaboration with Massimo Mariani, a heart surgeon at Medisch Spectrum Twente, a regional hospital in the Netherlands. According to the protocol, approved by a hospital ethical panel, 10 myocardial infarction patients were to be injected with their own bone marrow cells. The trial was halted in March, however, after a second review by the Dutch Central Committee on Research Involving Human Subjects (CCMO), which criticized the poor trial design, the ill-defined role of Cells4Health, the risks to patients, and the poor information they received. Mariani, who strongly disagrees with the verdict, says eight patients had already been treated before CCMO panned the study; he intends to publish the results.

    In a regional hospital in Belgium, meanwhile, Cells4Health tried to set up a trial in stroke and spinal cord injury patients. Again, the trial design was poor, and there was “no scientific basis whatsoever,” says Catherine Verfaillie, a stem cell researcher of Belgian origin at the University of Minnesota, Twin Cities, who was asked to review the study by the hospital. The trial was canceled. Cells4Health Director Kleinbloesem, citing recent “bad experiences” with the press, declined to be interviewed.

    Regulatory patchwork

    It's no coincidence, critics say, that most stem cell treatments take place in less-developed countries, where regulatory systems are weaker. But even in Western countries, cell-based treatments often fall into a regulatory gap.

    Recently, U.S. Food and Drug Administration (FDA) agents investigated Biomark International, a company in Atlanta, Georgia, that provided stem cell therapies for ALS and other diseases. A 51-count indictment returned by a grand jury on 28 March charged that among other things, Biomark's founders, Laura Brown and Stephen van Rooyen, lured patients with “false, misleading, and inaccurate statements on the Biomark Web site and in other advertisements.” A successful prosecution could put the duo in jail for many years. The pair is now wanted by federal authorities.

    According to media reports, Van Rooyen returned to his native South Africa, and Brown is now involved in Advanced Cell Therapeutics (ACT), a company with a mailing address in Switzerland and a telephone number in London that the British MS Society says has treated well over 300 MS patients from the United Kingdom. (Its name resembles that of Advanced Cell Technology in Worcester, Massachusetts; the company was alerted to the existence of a second ACT only weeks ago, says Vice President of Research and Scientific Development Robert Lanza.)

    According to a Web site maintained by Advanced Cell Therapeutics, its clinical procedures take place in 12 locations around the world, from Mexico and Argentina to Thailand and Pakistan. One of the clinics on the list is PMC in Rotterdam; ACT also provides PMC with its stem cells, says Trossel. Another one of ACT's collaborating clinics, in Cork, Ireland, is now under investigation by the Irish Medicines Board. (ACT offered to respond to questions sent by e-mail but didn't respond to e-mails or follow-up calls from Science.)

    In response to media stories about stem cell companies, both the British and Belgian governments recently announced new rules to limit their activities. In the Netherlands, neurologist Rogier Hintzen of Erasmus Medical Center in Rotterdam prodded authorities last year to look at therapies offered by Cells4Health and PMC. A Dutch Health Inspectorate spokesperson says an investigation will be finished this summer. Pending the outcome, however, the agency issued an unusual letter to patients warning that there “is no scientific proof” for the treatments and that “skepticism and caution are in order.” Elsewhere in Europe, stem cell treatments are governed by a patchwork of laws—or none at all. That could change; in order to facilitate Europe-wide market access for so-called advanced therapies, the European Commission recently proposed uniform new regulations, which include a new scientific panel at the European Medicines Agency in London to assess therapies. But its adoption could take years, and it's not clear it will cover work by clinics such as PMC.

    And even if regulations are tightened up in Europe, it may be impossible to ban companies from flying patients to other countries for treatment, as Cells4Health does. The same is true in the United States: Medra, a company in Malibu, California, that says it has treated more than 1000 patients using fetus-derived stem cells, performs its procedures in the Dominican Republic.

    Still waiting

    Many stem cell companies quote recently published scientific studies on their Web sites. But at least one scientist has objected to being linked to what she considers a dubious company. Verfaillie says she was “horrified” when Biomark International cited her research on multipotent adult progenitor cells on its Web site. Her university alerted FDA multiple times, she says. Today, ACT uses the references to Verfaillie's work in its patient package.

    Some say that scientists themselves may be partly to blame for the growing popularity of unproven therapies. The tremendous hype surrounding stem cells “has created very unrealistic expectations in patients,” says neurologist Neil Scolding of the University of Bristol, U.K.—adding that researchers, politicians, and the media all bear some responsibility. “It's like the dot-com bubble,” says Raisman. But others disagree. “The scientific community has been trying hard to educate the public,” says Lanza; the field shouldn't be judged by “one or two bad apples,” he adds.

    Spreading hope.

    Personal stories have fueled interest in companies such as Advanced Cell Therapeutics, which is believed to have treated more than 300 British MS patients.

    CREDIT: COURTESY OF THE SUNDAY TELEGRAPH, LONDON (29 JANUARY 2006)

    Still, scientists are finding that they have to throw cold water on the high hopes. At the request of the Association of British Neurologists, Scolding is currently drawing up guidelines for doctors confronted with MS patients inquiring about cell treatments. The sad message, he says: They just have to wait. There is no treatment yet.

    John Franken is still waiting, too. Almost 6 months after his operation in Azerbaijan, he has noted some changes: One toe has become hypersensitive, for instance, and he can feel temperature changes in his left leg and knee. He hasn't regained control of his paralyzed muscles, however.

    After his telephone interview, he asked Science in an e-mail not to write a negative story about Cells4Health. Scientists should give Kleinbloesem, “a courageous pioneer,” a fair chance, says Franken, who says he may return to Baku: “I simply refuse to accept that I have to live like this the rest of my life.”

  10. NANOTECHNOLOGY

    Pretty as You Please, Curling Films Turn Themselves Into Nanodevices

    1. Adrian Cho

    Nanometer-thick films that roll themselves into tubes and fold up into elegant shapes promise a highly controllable way to make tiny gadgets

    Sometimes the results of an experiment are so beautiful that researchers assume they must be useful, too. Just ask Detlev Grützmacher. Six years ago at a conference in St. Petersburg, Russia, Grützmacher, a physicist at the Paul Scherrer Institute in Villigen, Switzerland, spied images of the nanometer-sized tubes and helices a Russian colleague had fashioned from films of semiconductor, the stuff of microchips. The gracefully curling objects resembled modern sculpture.

    “Immediately, I started fantasizing about what kind of things one could do with these,” Grützmacher says. “Can I make a capacitor? Can I make an inductor? A sensor?” Now, he and a small but growing number of other researchers hope to turn the curlicues into a new form of nanotechnology.

    For more than a decade, physicists and engineers have strived to make nanometer-sized gizmos. Some etch ever-smaller devices out of semiconductors, a “top-down” approach that seeks to raise three-dimensional (3D) structures from a succession of layers. Many are exploring a “bottom-up” approach that aims to assemble devices out of individual molecules, such as superstrong carbon nanotubes. To make a practical technology, however, researchers must coax the molecules to piece themselves together, and such self-assembly remains a distant goal.

    But a handful of researchers think they can enjoy the best of both worlds. They are experimenting with films that roll themselves into delicate tubes or fold like minuscule cardboard boxes. The budding technology—known as strain architecture, rolled-up nanotech, or nano-origami—offers lithography's ability to put things exactly where they're needed. At the same time, the films curl themselves into novel 3D structures, adding an element of self-assembly.

    “It's a whole new direction,” says Max Lagally, a materials physicist at the University of Wisconsin, Madison. “Here you really have a way to make the same thing over and over with interesting properties that you can control.” Pablo Vaccaro, a physicist with the Advanced Telecommunications Research Institute International (ATR) in Kyoto, Japan, says the relatively simple and flexible technology will surely find applications. “I feel that we are just at the beginning of a big wave that will revitalize the field of semiconductors,” he says.

    That wave is still more of a ripple than a whitecap. Rolled-up nanotech probably won't wind its way into production lines for years. But proponents say the self-rolling tubes and helices may have more potential than competitors such as carbon nanotubes. Force sensors, tiny inkjet printers, and other experimental devices based on the wound-up technology may be around the corner.

    Spring loaded.

    When a film is freed, its top layer contracts, and its bottom layer expands, causing the film to curl and roll.

    CREDITS (TOP TO BOTTOM): ILLUSTRATION: P. HUEY/SCIENCE; REPRINTED FROM O. G. SCHMIDT ET AL., PHYSICA E 13, 969–973 (2002) WITH PERMISSION FROM ELSEVIER

    Rolling out of Siberia

    The technology was born by accident, in the laboratory of Victor Prinz, a physicist at the Russian Academy of Sciences Institute for Semiconductor Physics in Novosibirsk. In 1995, Prinz and colleagues were studying how electrons hop across a crack in a suspended film of semiconductor. They knew that a film consisting of two layers of different materials should bow, potentially allowing researchers to control the width of the crack. To their surprise, the “bilayer” curled into a tube.

    That happens because the layers contain atoms of different sizes. For example, to form a film, researchers may lay down a layer of silicon mixed with germanium and top it with a layer of pure silicon, depositing the layers on a soluble “substrate.” The atoms in the film arrange themselves in orderly arrays like oranges stacked neatly at a fruit stand. But because germanium atoms are bigger than silicon atoms, atoms in the silicon and germanium layer have to squeeze together and the atoms in the silicon layer have to stretch apart. So when researchers etch away the substrate, atoms in the upper layer snap back toward one another and those in the lower layer spring apart, causing the film to curl upward.

    Theorists predicted that it would be impossible to etch away the substrate without damaging the film, or that films only a few layers of atoms thick would quickly oxidize, Prinz says. Yet, within a few years, he and his team had wound up tubes, coils, and helices with widths ranging from a few micrometers down to a few nanometers. “Never trust theorists in novel fields,” Prinz says. “Trust only in your experiments.”

    As unlikely as it sounds, such films wind themselves into tight spirals resembling carpet rolls, with successive windings binding neatly to each other. Researchers can form more complex shapes such as helices by exploiting the fact that the films tend to curl perpendicular to certain rows of atoms, just as a carpet might roll most easily perpendicular to its warp. If researchers lay down a thin strip of film that's canted relative to the easy-rolling direction, it will curl into a helix instead of a tube.

    The roll-up technique offers several advantages, proponents say. The approach begins with standard lithography to pattern films and etch away substrates, so it provides the exquisite control of that tried-and-true technology. The basic physics is so simple that the approach should work with a wide variety of materials. And because the technique works with semiconductors, it should be possible to roll up electronic circuits in the film or to integrate tiny tubes, coils, and other devices directly into microchips—at least that's the hope.

    What's it good for?

    For the moment, researchers are primarily studying the electrical, optical, and mechanical properties of the tubes and other shapes they've made. Two years ago, physicist Oliver Schmidt and colleagues at the Max Planck Institute for Solid State Research in Stuttgart, Germany, showed that a rolled-up nanotube can convey liquid like a tiny pipe. Earlier this year, they reported in Applied Physics Letters that the tubes also guide light like optical fibers.

    Schmidt and colleagues have recently rolled up films of a single material. They grow the film so thick that the atoms near the bottom squeeze together but those near the top feel no pinch. That's because faults develop in the stacking that allow the upper atoms to shift apart, Schmidt reported at a meeting of the American Physical Society in March. The advance could lead to a handier all-silicon technology. The tubes can also emit light, Schmidt says, a trait that could lead to rolled-up lasers on a chip, a potential boon for “optoelectronics.”

    Researchers have rolled up a variety of materials, including metals and insulators. The technique even works with polymers, physicist Manfred Stamm of the Leibniz Institute of Polymer Research Dresden in Germany and colleagues reported last year in Advanced Materials. They lay down a polymer that absorbs a solvent and swells, then top it with one that does not; the swelling curls the film. “Millions of different polymers exist with all sorts of functionalities,” Stamm says, “and interfacing to biological systems may be easier because most biomaterials are polymers.” Stamm hopes to use a polymer nanotube as the nozzle for a nano-inkjet printer that might spit out one macromolecule at a time.

    Some researchers use curling films to connect larger plates and fold them into micrometer-sized devices in an approach known as nano- or micro-origami. ATR's Vaccaro and colleagues have used semiconductor films to make an array of pop-up mirrors and other structures without complex hinges or moving parts. Optics engineer George Barbastathis and colleagues at the Massachusetts Institute of Technology in Cambridge have made tiny fold-over capacitors, as they described in Applied Physics Letters in February, and the team's ultimate goal is to fold up accordionlike devices that manipulate light in novel ways. “We see this as an enabling technology,” Barbastathis says. “We're trying to make it as manufacturing applicable as possible.”

    Les objets.

    Using the curling films and a little ingenuity, researchers can create a wide variety of potentially useful shapes, such as a grasping claw, a suspended spiral, and a delicate coil spring. The same basic physics can be used to make larger folding or pop-up structures, such as a microstage.

    CREDITS (GROUP, TOP ROW AND BOTTOM RIGHT): L. ZHANG AND D. GRÜTZMACHER/PAUL SCHERRER INSTITUTE; (GROUP, BOTTOM LEFT) T. LEISCHMANN, K. KUBOTA, P. O. VACCARO, AND S. SARAVANAN

    Experimental widgets based on the new technology are already starting to emerge. Physicists Tobias Kipp, Detlef Heitmann, and colleagues at the University of Hamburg in Germany have turned a semiconductor tube into an optical ring resonator, a device that resonates with light much as a whistle rings with sound. Described in Physical Review Letters in February, the resonator isn't yet as good as those made by other techniques. But the researchers think rolled-up resonators could someday play a part in quantum information technologies.

    Employed like a probing finger, a drill-like helix should also make a good force sensor, says Bradley Nelson, a roboticist at the Swiss Federal Institute of Technology (ETH) in Zurich. Because the tubes bend much more easily than the probes used on atomic force microscopes, such a sensor should be extremely sensitive, says Nelson, who is collaborating with Grützmacher of the Paul Scherrer Institute. The team should have a working sensor within 6 months, Nelson says.

    Perhaps most ambitiously, applied physicist Robert Blick and colleagues at the University of Wisconsin, Madison, hope to use free-floating silicon germanium tubes as chemical sensors that unwind when they encounter their target molecule. Researchers already do something similar with fluorescent quantum dots, whose light changes when the dots bind to their chemical target. The tubes “are a bit bigger, but they're a lot more flexible in that they can change their shape and you can incorporate electronics,” Blick says. The project is in its early stages, but the researchers have shown that they can wind and unwind a tube by changing the salinity of the solution surrounding it.

    Tube versus tube

    Amid the parade of grand visions, some researchers say it's too early to tell whether the roll-your-own approach will pay off. “I don't see how one can claim it has any advantages versus bottom-up approaches, since neither has been demonstrated,” says Charles Lieber, a chemist at Harvard University. Even the optimists acknowledge that technical hurdles lie ahead. For example, affixing electrical contacts to rolled-up devices can be tricky.

    Researchers working with the curling films disagree on how they stack up against other forms of nanotechnology, in particular carbon nanotubes. The bizarre, elongated molecules of carbon possess electrical and mechanical properties that the larger semiconductor nanotubes cannot hope to match, says Wolfgang Hansen, a physicist at the University of Hamburg whose team has rolled up tubes containing layers of metal and insulator. “The bandwidth for applications is certainly larger” for carbon nanotubes, he says. ETH's Nelson, who works on both types of tube, sees it the opposite way. “There's just a lot more design possibilities with these little coils,” he says. “There are a lot more materials and interesting geometries that you can produce.”

    CREDIT: L. ZHANG ET AL., NANO LETT. 6 (2006), ACS

    All agree that finding a few killer applications would go a long way toward transforming vision into reality. Researchers can't yet say what those could be—perhaps something as simple as tiny inductive coils for electronics—but most are hopeful that they will come. The tale of this technology, they say, has only begun to unwind.

  11. SCIENCE EDUCATION

    A Strategy That Works: Hook 'Em While They're Young

    1. Jerry Guo*
    1. Jerry Guo is a freelance writer in New Haven, Connecticut.

    A groundbreaking program is giving Chinese high schoolers a chance to try their hand in a university lab—and audition for roles in China's innovation drive

    SHANGHAI—While his friends were babysitting or waiting tables, 18-year-old Jim Liu spent his summer vacation last year in Boston, developing software that allows children to construct LEGO Mindstorms robots able to do everything from play soccer to dispense candy. Liu, a native of Shanghai, was one of 88 teenagers from across the world selected for the Research Science Institute (RSI), an all-expenses-paid summer program at the Massachusetts Institute of Technology (MIT). Now back home, Liu is hoping some of the excitement he felt will rub off on fellow teens in China. He's a counselor with the inaugural RSI-China, which began last week here at Fudan University and will run through 15 August.

    Showtime.

    Jim Liu (above, center) demonstrates his summer project to fellow students at MIT. He hopes his enthusiasm will infect compatriots at Fudan University (right).

    CREDITS: JIM LIU; (INSET) CAIO CAMARGO

    The program is trailblazing in other ways: It's the first time a Chinese university has partnered with a U.S. organization to sponsor a high-school program. Run by the Center for Excellence in Education (CEE), a nonprofit organization based in McLean, Virginia, and Fudan University, RSI-China aims to build on the success of its flagship MIT program to train innovative young Chinese minds. “High-school students bring a new perspective [to the lab], and a new discovery is even possible,” says Lu Fang, physics dean at Fudan and co-director of RSI-China.

    For 6 weeks, 35 of the brightest high-school juniors in Shanghai will experience a reprieve from cramming for university entrance exams to work in Fudan labs. They will also attend classes and lectures on hot research areas. Half the Shanghai staff are graduates of the MIT program. RSI-China culminates with students presenting findings in talks and undergraduate-level term papers. This format has worked well for RSI-MIT, which has had an impressive track record over its 23-year lifetime for hooking students on science: Some 80% of alumni have gone on to graduate school in the sciences.

    Following the success of similar programs in Boston, Bulgaria, Israel, and Singapore, CEE sought a foothold in China and got a warm welcome from the government. A philanthropist steered CEE to Fudan, where university administrators were eager to host RSI-China. They see it as a way to hold on to some of Shanghai's top students, many of whom end up in Beijing at Qinghua University or Beijing University. To bankroll the program's first year, organizers signed up local backers: Shanghai Educational Press Group and Shanghai Wall Street Advisors.

    RSI-China applicants faced stiff competition. More than 30 schools across Shanghai nominated their top 10 students, although the program could accommodate only 10% of this elite pool. CEE staff interviewed each student to find those with a passion for science outside the classroom, Lu says.

    Fudan professors say they welcome the opportunity to work with talented high schoolers. “It's a very good idea. They can already start doing interesting stuff,” says Rudolf Fleischer, a computer scientist at Fudan who has volunteered to mentor one student on a project employing computational geometry to improve optical character recognition. “My goal is to show them what happens at university, because if you start early, you get better students,” Fleischer says. For many Chinese professors, he adds, mentoring is a new skill: “Traditional Chinese education is based on memorizing. Mentoring is not a concept that many Chinese professors understand well.”

    RSI-China is a small step toward addressing a widespread shortcoming of Chinese schools: Few offer hands-on science instruction, let alone lab facilities. “This is a very different concept for educating students in China,” says CEE President Joann DiGennaro. The main aim in Chinese schools is to hone test-taking skills, says Liu. After RSI, he says, “creativity will be activated. Now, all that high-school students seem to think about is the entrance exam, and that's not good.” After spending the 2004-'05 academic year as an exchange student at T. C. Williams High School in Alexandria, Virginia, Qian Yingzhi, a member of RSI-China's inaugural class, says she appreciates the rare invitation to work in a Chinese lab. “I want to expand my horizons,” she says.

    The projects are “real research that we undertake every day,” says Yang Zhong, executive dean of life sciences at Fudan. He is hosting a student who will fish flavonoid genes out of Tibetan plants as part of a project to detect adaptation through molecular evolution. Other projects include working on solar energy cells, examining the nonlinear behavior of yeast cells zapped with electrical currents, and screening for microbes that break down pollutants.

    The grand challenge of RSI-China is to facilitate the exchange of ideas with the international community, says Lu. “China is an emerging world power in academics,” adds DiGennaro. She hopes the program will be able to improve international relations between China and the United States while teaching students to think on their own. Lu agrees that this is a worthwhile aim. “We don't want the professor to teach the student but rather the student to teach himself,” he says.

    Lu has lofty aspirations for RSI-China. If all goes well this summer, he hopes that next year the program can recruit students from across the country. For Liu, the taste of real research last summer impelled him to pursue a science career in the United States; as a first step on that journey, he is enrolling at MIT this fall. He hopes the experience will be equally motivating for RSI-China's freshman class. At least it will be a refreshing break from having to memorize their science textbooks.

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