News this Week

Science  05 Dec 2008:
Vol. 322, Issue 5907, pp. 1446

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    Three Asian Nations Link Up to Form a Formidable Radio Telescope Array

    1. Dennis Normile

    SEOUL—The hill smack in the center of Yonsei University here gives a spectacular view of the school's gardenlike campus and, in the distance, downtown Seoul. Astronomers from South Korea and across Asia also hope this vantage point will offer an arresting view of the heavens. A 21-meter radio antenna perched on the hilltop is part of Korea's first very long baseline interferometry (VLBI) array, completed this week.

    Linked to arrays in Japan and China, Korea's three instruments will fill out the densest network of its kind, says Hideyuki Kobayashi, a radio astronomer at the National Astronomical Observatory of Japan in Mitaka. The East Asia VLBI Network comprises 19 antennas scattered over 6000 kilometers, from Urumqi in northwestern China to Japan's remote Ogasawara Island, and from Hokkaido to Kunming in China's southwest. A rival to U.S. and European networks (with 10 and eight instruments, respectively), the East Asia VLBI is expected to put Asian astronomers at the vanguard of mapping stars and galaxies and studying active galactic nuclei and other exotic objects.

    The three national arrays of the East Asia network were conceived independently but work well together. Japan brought its VLBI Exploration of Radio Astrometry (VERA) network of four 20-meter antennas online in 2004. Its primary objective is to construct a precise three-dimensional map of the Milky Way. For some observations, VERA's power can be augmented by eight radio telescopes in Japan. In 2006, China built a 50-meter radio telescope in Beijing and a 40-meter dish in Kunming, complementing existing 25-meter radio telescopes in Shanghai and Urumqi, to track the Chang'e-1 spacecraft now orbiting the moon. And on 2 December, Korea completed construction of the last of three 21-meter telescopes in its Korean VLBI Network (KVN). Like the dish at Yonsei, the other two are on university campuses “to make it easy to interest students in astronomy,” says Hyo-Ryoung Kim, director of radio astronomy for the Korea Astronomy and Space Science Institute in Daejeon.

    Tuning in.

    Hyo-Ryoung Kim expects South Korea's three 21-meter antennas to play a pivotal role in a new Asian array.


    The idea to link arms grew out of discussions over several years at triennial meetings of the East Asian Network of Astronomy, which brings together researchers from China, Taiwan, Korea, and Japan. (Taiwan does not have a radio antenna.) People realized that it was time to coordinate facilities “to go for some more ambitious projects,” says Zhiqiang Shen, an astronomer at Shanghai Astronomical Observatory.

    One primary target of the East Asia VLBI Network will be extending and refining VERA's effort to map the Milky Way. VERA has achieved noteworthy results in locating stars, but adding KVN will double the accuracy, Kobayashi says. Their aim is to locate each star to 10% accuracy—“a unique and challenging effort that will give us very good information about the structure of the galaxy,” he says. Plotting the evolution and movement of stars, he adds, will “reveal the dynamics of the galaxy very precisely.”

    Astronomers expect the East Asia VLBI to quickly make its mark. “The structure of the Milky Way, how massive stars form, the history and fate of local galaxies, is quite a rich field,” says Mark Reid, a radio astronomer at the Harvard-Smithsonian Center for Astrophysics in Cambridge, Massachusetts. The new Asian array will “be a big player in that effort.”

    Achieving the target accuracy depends on a technique known as phase referencing to correct for atmospheric distortions. In this regard, the new network does not mesh seamlessly, because the Japanese and Korean telescopes use different schemes. Japan's relies on simultaneously observing two celestial objects: the target and a well-characterized reference. Data gathered from the target can be corrected based on distortion of the reference object. Korea's scopes simultaneously observe a single target at four frequencies—22, 43, 86, and 129 gigahertz—something no other telescope can do. Higher frequencies are more sensitive to atmospheric disturbances, so observations at lower frequencies are used for corrections. In principle, the two techniques can be combined, says Kobayashi. “But we have to show it can really be done.” The group tried to combine observations from Yonsei and a VERA antenna for the first time in late October. “The image is still a bit dirty, but scientifically it is okay,” says Kim.

    A second objective is studying active galactic nuclei (AGNs), supermassive black holes surrounded by accretion disks, and jets of material ejected at relativistic speeds. AGNs are believed to lie at the center of most galaxies. “There are many theoretical predictions about the structure and the temperature and the phenomena happening around AGNs, but no one has resolved these problems,” says Kobayashi. To try to answer the questions, the East Asia VLBI Network plans to work with VSOP 2, a radio antenna Japan plans to put in orbit in 2012.

    Even before then, KVN's observations at four frequencies, simultaneously capturing data on energy emitted at four wavelengths, could lay bare the inner workings of AGNs. According to Philip Edwards, head of scientific operations for the Australia Telescope National Facility's Paul Wild Observatory in Narrabri, such measurements are important for understanding transient phenomena such as bursts and flares. “If you're going to model (the phenomena), the more simultaneous data the better,” he says.

    Although the Korean network is complete, there is still much work to do. To combine data from the national arrays, Japan and Korea plan to jointly build a correlator—a specialized computer—in Seoul. They hope to have it running by the end of next year. Meanwhile, for the next several months, the priority for China's radio telescopes will be tracking Chang'e-1, says Shen. Full-fledged observations using the East Asia VLBI Network are expected to get under way in 2010. When that happens, the view from Yonsei's hill campus will be all the more spectacular.


    Ministers Bankroll European Space Agency's Ambitions

    1. Daniel Clery

    Europe's space scientists are breathing a collective sigh of relief because the member governments of the European Space Agency last week gave ESA more or less everything it had asked for in funding for the next few years—a total of nearly €10 billion. At a key ESA budget meeting, European politicians approved a request from the agency's science program for modest annual increases and gave an ambitious environmental monitoring system the green light. Questions still hang over the troubled ExoMars mission slated for 2016, but researchers are now confident that it will survive. The United Kingdom also signed a deal to host an ESA facility, which will end the embarrassment of the U.K. being the only major funder of the agency without a facility on its soil. “People are very happy indeed. It seems a win, win, win situation,” says George Fraser, director of the Space Research Centre at Leicester University in the U.K.

    Ministers from ESA's 18 member governments meet every 3 years or so to agree to its budget, and there were concerns ahead of last week's meeting in the Dutch port city of The Hague that the world financial crisis would limit governments' generosity (Science, 21 November, p. 1180). Yet after more than a decade of flat budgets, ESA's science program will now enjoy a gradual ramping up of its resources by 3.5% per year. Obtaining that funding boost was crucial, says Alan Smith, director of the Mullard Space Science Laboratory of University College London, because some of ESA's science missions awaiting approval, which include space telescopes, planetary missions, and an exoplanet finder, have grown overly ambitious and over budget. “To avoid collapse, we needed this uplift.”

    The ExoMars mission also received news that was as good as most could hope. The first part of the Aurora program of solar system exploration, ExoMars had swollen from the budget of €650 million approved 3 years ago to somewhere near €1.2 billion. Ministers balked at that sum and granted just €850 million, but the account will be left open for the next year as ESA reconfigures the mission and looks for international partners. “I hope there will be no descoping,” says astrophysicist Jean-Pierre Swings of the University of Liège in Belgium, who chairs the European Space Sciences Committee, an advisory body.

    Orbital plan.

    As part of Europe's Kopernikus program, the planned Sentinel-3 satellite would monitor ocean and land features such as surface temperature.


    The Kopernikus program, an ambitious plan to set up an environmental monitoring system for government and business users, fared better, winning €831 million—enough to launch the first few satellites and make the system operational. A dispute over who should pay for backup satellites, or b-units, was resolved with ESA footing the bill. “This is a very important program,” says Roger Bonnet, director of the International Space Science Institute in Bern and a former ESA science chief. “We need a [Kopernikus] for the whole world, not just for Europe.”

    One sour note at last week's meeting was an apparent lack of enthusiasm among the ministers for a plan to develop ESA's cargo vessel, the ATV, so that it can carry material back to Earth, and to conduct further studies on astronaut-carrying craft. These efforts won €62 million, less than half the amount requested. Bonnet says that Europe downplays human space flight because it does not have the “national pride” of the United States and Russia, or newcomers China and India. “Science and education are the priorities in Europe.”

    The U.K. delegation at The Hague came away happy, clutching an agreement for a new ESA research center focusing on climate change modeling using space data, robotic exploration, and developing power sources for deep-space craft. It will be based at the Harwell Science and Innovation Campus in Didcot, site of the Rutherford Appleton Laboratory. “There are an awful lot of things coming together for space in the U.K.,” says Smith. “Now we've got to deliver to make the most of it.”


    Less Vaccine Can Be More

    1. Martin Enserink
    Scarce commodity.

    People line up to receive meningitis shots in Aura, Uganda, in February 2007.


    The meningitis season has begun in Africa—and once again, it will be a tough battle. Health officials will use vaccines that act like fire brigades, squelching outbreaks where they erupt; but vaccine stocks are so tight, they have to be deployed sparingly, and there's always the danger of shortages.

    In a paper this week in PLoS Neglected Tropical Diseases, a team led by epidemiologist Philippe Guérin of Médecins Sans Frontières (MSF) shows a way to stretch those limited supplies. The team reports that just one-fifth of the standard vaccine dose triggers an immune response almost as good as that of the full dose. That means the stockpile of some 10 million doses that will be available this season might be used to vaccinate as many as 50 million people.

    The idea has excited meningitis experts in and around the World Health Organization (WHO). But it has also triggered controversy. The main vaccine manufacturer, Sanofi Pasteur, worries about liability problems and wants nothing to do with the strategy. Switching doses is a logistical challenge as well and can be politically risky if it is seen as lowering the level of care. Still, WHO is laying the groundwork for a move to “fractional doses” if shortages occur, says WHO meningitis expert William Perea.

    Immunity from the current generation of polysaccharide vaccines against Neisseria meningitidis lasts just 3 years or so, which is why the shots are used reactively to contain an outbreak rather than to prevent one. The vaccines are of little interest to companies because they are used in the poorest countries in the world—those in Africa's “Meningitis Belt”—for less than $1 a dose. Moreover, new, more powerful “conjugated” vaccines may soon make polysaccharides obsolete (Science, 27 June, p. 1710). For now, WHO has struck a deal with two manufacturers—Sanofi Aventis and Bio-Manguinhos in Brazil—to keep producing the vaccines for an emergency stockpile, managed jointly by WHO, UNICEF, MSF, and the Red Cross/Red Crescent.

    Hints that fractional doses might work almost as well emerged from studies on U.S. military recruits in the 1970s and '80s. In the current study, researchers tested the same idea among 750 healthy volunteers ages 2 to 19 in Uganda, using a Sanofi Pasteur vaccine that protects against four different meningitis serotypes. One-fifth of the standard dose triggered antibodies against the A strain—by far the most prevalent in Africa—almost as well as the full dose; for two other strains, W135 and Y, one-tenth was enough.

    In December 2006, Guérin presented the results to a panel of experts assembled at WHO's request to decide whether fractional doses could be used in the 2006-07 season. Yes, the panel said: During shortages, the benefit to the population as a whole would outweigh a slightly increased risk for individual vaccinees. But the operation wasn't needed that year or the following because there was enough vaccine.

    A spokesperson for Sanofi Pasteur says the company can't prevent WHO or individual countries from using the vaccine however they want, but it “cannot endorse” anything except using the licensed dose. The company has warned WHO about legal risks the agency may face by recommending fractional doses, says Alejandro Costa, a scientist at WHO. (A spokesperson at Bio-Manguinhos did not respond to requests for comment.)

    Perea says WHO will recommend fractional doses if necessary this winter. But expanding the vaccine supply should be the main goal, he says. Because a full dose is still the safest bet, using fractional doses “will remain the joker card that we play only when we really have to.”


    In Rare Encounter, U.S. and Chinese Scientists Craft Nuclear Glossary

    1. Richard Stone1
    1. 1With reporting by Rachel Zelkowitz.

    BEIJING—What does nuclear deterrence mean? An active defense? Strategic defense? What constitutes a nuclear explosion? Precise definitions are critical for everything from negotiating treaties to interpreting military postures of ally and adversary alike. On 20 November, the U.S. National Academies unveiled the first Chinese-English glossary of nearly 1000 nuclear-security terms.* The compendium seeks to reduce misunderstandings between China and the United States—nuclear powers that came into conflict in the Korean War and could conceivably be in confrontation again. “Words count, and it matters how we use them,” says Raymond Jeanloz, a condensed matter physicist and national security expert at the University of California, Berkeley.

    The glossary is also the first open publication of a unique forum for Chinese and U.S. nuclear weapons experts. It's a “successful collaboration in a rather sensitive field,” says nuclear physicist Richard L. Garwin, fellow emeritus at IBM's Thomas J. Watson Research Center in Yorktown Heights, New York. But prospects for building on the glossary to expand such contacts in the near future appear dim.

    Chinese and U.S. nuclear-weapons scientists have had few opportunities to meet in recent years, especially after a U.S. congressional panel, chaired by then-Representative Christopher Cox (R-CA), alleged in 1999 that China had been stealing U.S. nuclear secrets for years. The Chinese government flatly denied the allegations, asserting that its nuclear program is wholly indigenous. Since then, both sides have largely forbidden contact between their nuclear-weapons communities.

    Fine point.

    “Active defense” has a specific meaning if applied to ballistic missiles such as the Minuteman III.


    One permitted tête-à-tête has been a dialogue between the academies' Committee on International Security and Arms Control (CISAC) and the Chinese Scientists Group on Arms Control (CSGAC). Private meetings between the two sides began in 1988 and survived the post-Cox Report chill. The discussions are confidential, but it's expected “that each side will report matters of significant interest to its government,” says Garwin, manager for the U.S. side. At a meeting in Vancouver, Canada, in 2006, the forum agreed to open up a bit and produce the glossary. They invited experts from outside CISAC and CSGAC to propose terms and help review the glossary before release.

    Although most terminology was amenable to straightforward translation, several dozen terms have different meanings depending on the context, or various implications in each language. For example, “active defense” has three definitions. China uses the term to describe its military strategy: “gaining mastery only after the enemy has struck” and “using active military preparations and political struggle to prevent war.” To U.S. experts, the term means “the employment of limited offensive action and counterattacks to deny a contested area or position to an enemy.” A third meaning of “active defense” relates to missile defense.

    For a few terms, the panelists hammered out translations but disagreed on the connotations. “There's a big difference of opinion about what 'deterrence' means,” says one U.S. nuclear analyst. “The Chinese think it's a bad word, that it means 'coercion.'” But in the U.S. view, she says, deterrence is a virtuous principle that has kept nuclear powers from annihilating one another. The two sides failed altogether to find common ground on a definition of limited deterrence.

    Discussions were sometimes heated but always collegial, says Jeanloz, a CISAC member who served on the glossary panel. And there's room for a more inclusive meeting of the minds. The academies asked experts from both countries for comments on the glossary over the next year. “This is the beginning of an important dialogue,” Jeanloz says.

    Serious barriers impede deeper interactions between Chinese and U.S. nuclear scientists, says Li Bin, director of the arms-control program at Tsinghua University's Institute of International Studies in Beijing. “The real obstacle is the Cox Report and its product, the new visa system in the name of antiterrorism,” he says. (U.S. security agencies submit visa applications of scientists from China and certain other countries to extra scrutiny; Science, 21 November, p. 1172). “That prevents scientists of the two countries from talking to each other more,” Li notes. Still, he and others say that the glossary marks a significant advance in the expansion of contacts—and trust—between two formidable communities of nuclear scientists.


    Fetal Immune System Hushes Attacks on Maternal Cells

    1. Mitch Leslie

    A baby developing in the womb receives from its mother not only nutrients but also some of her cells that sneak through the placenta and survive. Such maternal crossover cells were discovered more than a decade ago, and now on page 1562, researchers provide an explanation for why they escape attack by the fetal immune system. The work also suggests a new mechanism for how the human immune system learns to spare the body's own tissues, a tolerance that breaks down in autoimmune diseases.

    The new study shows that the maternal escapees spur the baby to produce regulatory T cells, or T regs—white blood cells that can quell immune assaults. T regs are one of the hottest topics in immunology, and the authors suggest that the fetus also depends on these pacifists to become tolerant of its own cells. Immunologists Jeff Mold and Joseph “Mike” McCune of the University of California, San Francisco, and colleagues report that T regs that arise in a fetus can linger within a child for years, perhaps undermining the effectiveness of vaccines.

    Other immunologists praise the study for bolstering the evidence of a robust human fetal immune system and revealing that the developing baby may have more than one way to keep it in check. “It's a definite advance,” says immunologist J. Lee Nelson of the Fred Hutchinson Cancer Research Center in Seattle, Washington, who has been studying fetal-maternal cell exchange for years.

    The paper extends a line of investigation that began with the discovery that fetal cells can persist in a mother's blood and tissue for decades and continued with the realization that this maternal-fetal cellular traffic went both ways. Last year, for example, work by Nelson and colleagues indicated that maternal pancreatic cells that had crossed the placenta were more common in patients with type 1 diabetes.

    How such maternal cells interact with a fetus's immune system remains unclear. The human immune system is hard to study in the womb, and researchers continue to debate how quickly it matures, in part because the widely studied rodent immune system doesn't become functional until after birth. To gain insight into the developing human immune system, Mold and colleagues began by probing how a fetus deals with maternal wanderers. The scientists obtained lymph nodes from second-trimester fetuses and discovered that maternal cells were much more common there than previous studies indicated. In one case, cells from mom constituted nearly 1% of the cells in the lymph nodes.

    So why doesn't the fetal immune system battle the maternal interlopers? Although a baby inherits half of its DNA from mom, her cells still sport many antigens, molecules that should trigger an immune attack. And Mold's team showed that fetal immune cells from the lymph nodes and spleen could recognize and respond to cells from unrelated adults.

    The researchers suspected that intervention by fetal T regs explained the forbearance toward maternal cells, in part because that would mirror what happens in the mother. One reason that a pregnant woman's immune system normally doesn't destroy the fetus is that her T regs defuse such attacks. Mold and colleagues were able to identify fetal T regs in the cultures of fetal lymph node cells. When they removed those T regs, cells from the lymph nodes reacted strongly to added maternal cells. These results raise “the possibility that there's more crosstalk between mother and fetus than we'd imagined,” says McCune.

    Close contact.

    Maternal cells cross the placenta into a baby but avoid attack by the child's immune system.


    If a fetus uses T regs to squelch immune assaults on maternal cells, it likely uses the same trick to dull immune attacks on its own cells, the researchers propose. Immunologists have long recognized that the developing immune system can kill off cells threatening the fetus's own tissues, but T regs would offer a gentler pathway to tolerance.

    The new study strengthens the case that the fetal immune system is no pushover, notes immunologist Rachel Miller of Columbia University. It isn't fully developed before birth, she cautions, but it's certainly able to put up a fight.

    Mold and McCune suggest that it's worth investigating the long-term health effects of T regs generated in the womb. Their team found that regulatory T cells tuned to maternal antigens were still detectable in children as old as 17. In some people, these enduring fetal cells could blunt responses to childhood vaccinations, the researchers suggest. But the cells may be useful, too, they speculate. Physicians could in theory exploit T regs to improve the prospects for fetal organ transplants by coaxing the baby's immune system to accept the implanted tissue.


    Treat Everyone Now? A 'Radical' Model to Stop HIV's Spread

    1. Jon Cohen

    Confronted with the lackluster success of HIV prevention efforts, researchers are increasingly pushing treatment itself as a way to slow the spread of the AIDS epidemic. The reasoning: Antiretroviral (ARV) drugs lower the amount of HIV in infected people, likely making them less able to transmit the virus. Now the World Health Organization (WHO) has published a provocative model that explores the possibility of “eliminating” the HIV epidemic by annually testing everyone on a voluntary basis and treating all infected people, regardless of their clinical status. WHO HIV/AIDS Director Kevin De Cock, who co-authored the study that appeared online 26 November in The Lancet, says, “What we hope to do is stimulate discussion.” And that they have.

    Testing and treatment on that scale would far surpass anything done today, but the payoffs could be huge, the authors say. According to their model, each untreated infected person infects seven others before dying. The study compares the impact of thwarting new infections when people start treatment at various stages of immune decline, and it assumes that treatment reduces a person's infectivity by 99%. Most poor countries can afford to treat only the people most in need, which is defined as anyone who has fewer than 200 CD4+ white blood cells, the critical immune warriors that HIV targets and destroys.

    As an example, the study focuses on South Africa, which has an adult prevalence of 17% and offers treatment at the higher cutoff, common in wealthy countries, of 350 CD4+s. At that point, the study calculates, an HIV+ person has infected three others. But if treatment started shortly after people became infected, the model suggests, on average, the person would infect less than one person each, and the severe South African epidemic would die out in 14 years (see graph). “If we really put our mind to it, we can do things people previously didn't think were possible,” says De Cock, noting that 3 million people in poor countries now receive ARVs that once were deemed impossibly expensive for them.

    All together now.

    Although ARVs still fail to reach many people in countries such as Myanmar (top), a model based on South Africa (bottom) shows that immediate treatment of the entire HIV-infected population could stop the epidemic there.


    Geoffrey Garnett, an epidemiologist at Imperial College London, St. Mary's, co-authored an accompanying editorial that called the strategy “extremely radical” for pushing public health over individual benefits: It remains unclear that early treatment delays disease and death, and it could increase the risk of drug resistance developing. It also raises other ethical, financial, and logistical dilemmas. And, Garnett contends, eliminating the epidemic is too ambitious a goal. But even if the strategy didn't reach all infected people, it might have a big impact on spread, he says. “It's not an idea to dismiss out of hand, but it's really challenging,” says Garnett. “The Lancet paper throws down the gauntlet to think about it.”

    Other research groups received little attention—or outright derision—when they published similar models a few years ago, but now, ARVs are less toxic and cheaper than ever, making the idea more realistic. Still, many question whether it could be pulled off. Today, an estimated 80% of the infected people in sub-Saharan Africa do not know their HIV status, and it's not simply a question of access to tests: In the United States, where testing is widely available, the Centers for Disease Control and Prevention says about 25% of infected people are unaware they are infected. Although the world has made much progress in delivering ARVs to poor countries, at the end of 2007, 6.7 million people who badly needed the drugs were not receiving them. Poor countries also typically use ARV regimens that are below the standards of those available in wealthy countries, which means toxicity and drug resistance remain serious issues for much of the world. In these countries, there are still staggering shortages of funds and trained people to test and treat. (Estimates suggest that by 2015, it will cost at least $41 billion annually to treat the 13.7 million HIV-infected people who then will have fewer than 200 CD4+s; wealthy countries currently donate some $10 billion.)

    De Cock and his coauthors did a preliminary cost analysis for South Africa that showed by 2015, the country would have to spend three times as much on testing and treatment as it does today. But because of declining infection rates, costs would then begin a steady decline.

    HIV/AIDS researcher Julio Montaner of the University of British Columbia, Vancouver, Canada, says he got “crucified” when he published a similar paper in The Lancet in 2006 and is “delighted” to see that WHO's “fancier” model supports his own. The key to the strategy, he contends, is cost: In the long run, it saves money. “Front-loading the investment on ARVs is a very wise investment, even in a time of financial crisis,” says Montaner. But he agrees that more data are needed to prove that starting treatment at the earliest possible point does not lead to toxicities and drug resistance that offset the long-term benefits. “How would you like it if I say, 'You don't qualify for treatment, but I want to treat you so you don't expose anyone else?'”

    De Cock says he would like researchers to launch small-scale trials of voluntary testing and immediate treatment to assess the impact on infected individuals and see whether it decreases the spread of HIV in populations, as the model predicts. WHO, he says, plans to hold a meeting early next year to discuss the strategy in more depth.


    Hopping to a Better Protein

    1. Elizabeth Pennisi

    Clinical trials are under way to test an innovative use of antisense technology to stem paralysis in Duchenne muscular dystrophy.

    Clinical trials are under way to test an innovative use of antisense technology to stem paralysis in Duchenne muscular dystrophy

    Healthy heart.

    The pink latticelike staining shows that antisense restored the protein dystrophin to this diseased mouse heart.


    Exon skipping. It sounds like a game, like hopscotch. But it's not child's play. A half-dozen research teams around the world are scrambling to turn exon skipping—which involves tricking a cell's protein-making machinery into skipping over defective parts of a gene—into a treatment for a devastating muscular disorder called Duchenne muscular dystrophy. “It's the best shot” for stemming the progressive paralysis that puts teenagers in wheelchairs and, in many cases, leads to premature death, says Eric Hoffman, a geneticist at Children's National Medical Center in Washington, D.C.

    A concept first demonstrated in the mid-1990s, exon skipping uses short stretches of DNA-like molecules called antisense to shut down a faulty section of a gene. In the past 2 years, promising results in animals and in cell-culture tests, as well as from a safety evaluation in people, have energized the muscular dystrophy community. Clinical trials of antisense drugs that home in on defects in the gene in Duchenne muscular dystrophy are now under way to assess how much muscle function can be restored. “A lot of things are jelling,” says Hoffman.

    Questions still remain. It's not clear how to reach all the body's affected tissue or how effective treatments will be over the long term. There is also much uncertainty about how these treatments would be regulated. “It's got a long way to go to determine whether it's going to be a drug or not,” says C. Frank Bennett of Isis Pharmaceuticals in Carlsbad, California, a company developing antisense drugs for other diseases. But a group of experts who met in Cold Spring Harbor, New York, in October to discuss the potential of exon skipping were optimistic that the obstacles are surmountable. Researchers understand the disease and the principles of exon skipping much better and have also improved antisense technologies, says Bennett. “It's sort of a three-part stool that's come together: All this progress is really beginning to pay off.”

    Tough disease

    Duchenne muscular dystrophy is the most common inherited childhood disorder. A sex-linked disease, it affects one in 3500 boys; without mechanical ventilation, death can occur before age 25. It is caused by mutations in the gene for dystrophin, a protein that helps stabilize the muscle cell membrane.

    In severe cases, the mutations lead to an aberrant molecule of messenger RNA (mRNA), which carries the instructions for making the protein to the ribosomes, the cell's protein-making factories. The result is a highly truncated dystrophin or no protein at all. Lacking functioning dystrophin, the muscle cell membranes leak, the muscles gradually waste away, and paralysis sets in. But some mutations result in a milder syndrome called Becker muscular dystrophy, in which the muscle cells produce dystrophin that isn't perfect but has enough activity to keep the muscle up and running.

    In the early 1990s, researchers in Japan and elsewhere began to explore exon skipping. One early convert, Steve Wilton, now a molecular biologist at the University of Western Australia in Perth, discovered that in a few muscle cells of patients with Duchenne muscular dystrophy or animal models of the disease, dystrophin was restored, suggesting that the faulty sections of the dystrophin gene were being bypassed. He wondered whether it was possible to trick all the muscle cells into skipping over the mutated regions to produce a functioning protein. “I knew what I wanted to do, but I wasn't sure how,” he recalls—until he heard Ryszard Kole of the University of North Carolina, Chapel Hill, describe how he had restored normal function to a mutated beta-globin gene using antisense technology in 1996. “It hit me like a brick” that the approach might work with dystrophin, says Wilton.

    In a normal cell, the gene's protein-coding regions—the exons—produce stretches of RNA that are spliced together into a single mRNA molecule. But mutations in one exon can lead to faulty mRNA and make it impossible for the protein-making machinery to read the rest of the mRNA strand. The idea behind exon skipping is to target the disruptive exon, or a nearby one, with antisense drugs, so it is not transcribed into mRNA (see diagram). The resulting mRNA would be missing a section, and the protein produced would lack some amino acids. But it would still function, much like the dystrophin in Becker muscular dystrophy.

    In a matter of months, Wilton and Kole had used antisense molecules to restore dystrophin gene function in cultured muscle cells, and a few years later, in live mice. His colleagues around the world were reporting similar successes, but Wilton had trouble getting support to follow up on the work. Antisense technology had been heavily touted in the early 1990s as a potential treatment for a variety of diseases, but it had not lived up to its promise (Science, 27 October 1995, p. 575). Wilton says one colleague even called exon skipping “a party trick.”

    The skepticism was well-founded. The cell membrane doesn't naturally let DNA molecules in because they may belong to a pathogen, yet antisense DNA needs to infiltrate the cell to do its work. That's less of a problem in muscular dystrophy because the disease makes the cell membrane leaky, but once inside, the foreign DNA must avoid being degraded by enzymes. To make matters worse, the quantities of an antisense drug required can stimulate a strong immune response. And because mutations can occur all over the dystrophin gene, an individual patient could require an antisense molecule targeted to any one of the gene's 79 exons.

    Better chemistry

    None of those problems deterred Wilton and others. They began designing DNA sequences that would bind very specifically to individual exons. Wilton now has 40 that he says are ready for clinical trials. At the same time, private companies began to harness ways to disguise the antisense molecules to avoid destruction by the body. The point is to have it “look less and less like a nucleic acid,” says Hoffman.

    The four bases that make up DNA hang off a molecular backbone that consists of alternating sugar and phosphate molecules. Taking one approach, AVI Bio-Pharma in Corvallis, Oregon, has replaced the pentagon-shaped sugar with a hexagon-shaped “morpholine” and substituted a linker called phosphorodiamidate for the phosphates. A Dutch biotech company, Prosensa, based in Leiden, has masked the sugar backbone by adding a methyl group.

    Gert-Jan B. van Ommen of Leiden University Medical Center in the Netherlands, another pioneer in exon skipping for muscular dystrophy, has been working with Prosensa for the past 5 years testing its antisense drug candidates. “We successfully get skipping in human and mouse cells and in vivo in mouse,” says Van Ommen. In 2006, he and his colleagues took the next step: They injected an antisense molecule targeted against exon 51 into the leg muscles of four patients and looked for the appearance of dystrophin at the injection sites. In each, “we got expression,” says molecular biologist Gerard Platenburg, Prosensa's CEO.

    The results, published in the 27 December 2007 issue of The New England Journal of Medicine, caused quite a stir. “After the paper came out with the beautiful pictures of dystrophin expression, the community as a whole has been excited,” says Jane Larkindale, research program coordinator for the Muscular Dystrophy Association in Tucson, Arizona. “[Duchenne muscular dystrophy] patients and their families are very eager to try any therapy that has potential to work.” Now Prosensa is midway through a larger study to determine the dosage requirements for effective treatment.

    In the United Kingdom, another research group is testing a morpholino antisense drug. Francesco Muntoni of the University College London Institute of Child Health and colleagues have injected the feet of five of seven patients and are planning a larger study that will involve periodic injections of 16 individuals.

    Qi Long Lu, a pathologist at Carolinas Medical Center in Charlotte, North Carolina, has added a peptide rich in the amino acid arginine to the morpholino antisense. It readily slips into the heart muscle in a mouse model of muscular dystrophy, he and his colleagues reported in the 30 September issue of the Proceedings of the National Academy of Sciences. That could be a big advance because previous studies have suggested it's almost impossible to get antisense molecules into heart muscle, which would be a major potential limitation to the utility of this therapy, Lu points out.

    Exon skipping.

    In this section of the dystrophin gene's pre-mRNA, introns are spliced out to make functional mRNA (A). But in muscular dystrophy, a mutation in exon 50 leads to a truncated and nonfunctional mRNA (B). Antisense knocks out exon 51, such that the remaining exons stitch together nicely, and the resulting mRNA leads to an altered dystrophin protein (C).


    Other approaches are in the works. Luis Garcia, a molecular biologist at the Institut de Myologie in Paris, is pursuing exon skipping with a twist. He has come up with a minigene that codes for an antisense molecule and is developing ways to transfer the gene into the patient's own muscle stem cells to create a more permanent source of error correction with just a single injection. The approach so far has restored dystrophin in a mouse model of muscular dystrophy using patients' cells, and he's trying it out in a dog model of muscular dystrophy, he says.

    Regulatory hurdles

    But even if antisense drugs are successful in mice, in dogs, and even in people, the nature of these small molecules is raising regulatory challenges. Because antisense drugs are a hybrid between a “biological” and a “small molecule drug,” it's not completely clear which regulatory rules apply. For example, the U.S. Food and Drug Administration guidelines for determining the correct drug dosages for humans based on animal studies might not work for these molecules, says Hoffman. Another concern is that an antisense drug might turn off an exon in another gene that has a very similar sequence to the target. Assessing that sort of toxicity will be hard to do in animals, in which such similar exons might not exist.

    Furthermore, these drugs will truly be “personalized,” as the antisense sequence must be tailored to the particular exon mutated in each patient. “For the rare mutations, there will not be sufficient patients to do a clinical trial,” says Larkindale. And some patients may require a cocktail of antisense molecules that will coordinate the skipping of more than one exon, complicating approval procedures even further.

    “There are lots of issues,” says Hoffman. Nonetheless, “you have to give Wilton and others a lot of credit for doggedly pursuing this and having it emerge as [the] winning horse.” And Wilton thinks more than Duchenne muscular dystrophy is riding on their work. Others are exploring using antisense technology to treat the blood disorder thalassemia, an aging syndrome called progeria, and another degenerative disease, spinal muscular atrophy. “If exon skipping does not work for Duchenne muscular dystrophy,” says Wilton, “I find it difficult to believe it could work for any other conditions.”


    Sanctuaries Aim to Preserve a Model Organism's Wild Type

    1. Robert Koenig

    The axolotl, a salamander that retains unique evolutionary features and is a darling of biologists because it can regenerate limbs, faces adversity on two fronts.

    The axolotl, a salamander that retains unique evolutionary features and is a darling of biologists because it can regenerate limbs, faces adversity on two fronts

    Beastly beauty.

    With its feathery gills and quizzical face, the axolotl is plausible as an Aztec god.


    MEXICO CITY—Leaning over the Traginera flatboat's edge, Luis Zambrano surveys a canal floating with plastic bottles, Styrofoam cups, and a leafy carpet of invasive lilies. African tilapia fish ripple the brown water's surface and a Chinese carp lurks underneath, but Zambrano sees no signs of his elusive goal: the axolotl salamander.

    “We've spotted only a few in 6 months,” says Zambrano, a freshwater ecologist at the National Autonomous University of Mexico (UNAM) who is trying to count and preserve the feathery-gilled, 33-centimeter-long salamanders in their only natural habitat, the Xochimilco network of polluted canals and small lakes in and around Mexico City, the world's third largest metropolitan area.

    Five hundred years ago, axolotls—named for an Aztec god who transformed into a water animal to avoid being sacrificed—were common in the lakes around the Aztec capital. But as the wetlands receded, so did the axolotls, to the point that Zambrano now estimates a population density of only 100 per square kilometer of wetland, compared with estimates 10 times higher in 2004 and another six times higher than that in the 1980s. The species, Ambystoma mexicanum, is now classified as critically endangered by the International Union for Conservation of Nature.

    A serious threat to axolotls could prove damaging to science, for the salamander has been used for more than a century as a model organism by developmental biologists. Even though the wild type's survival is threatened, thousands of axolotls are raised in laboratories every year for use in research projects involving regeneration, stem cells, and developmental biology. For example, more than 1000 adult and juvenile axolotls are maintained in aquariums at the University of Kentucky's Ambystoma Genetic Stock Center in Lexington, which distributes between 15,000 and 20,000 axolotl embryos each year to more than 100 research labs in India, Germany, Japan, Mexico, and elsewhere.

    Although they are propagated as aquarium pets and are considered easy to breed, some axolotl colonies in labs are now under threat from a puzzling disease. The Ambystoma center's director, developmental biologist Randal Voss, is concerned about what he calls a “mysterious epidemic”—it first emerged when the center was managed at Indiana University in the 1990s and reemerged a few years ago—that has been killing some axolotl larvae. He says, “Very little is known about disease and pathogens of lower vertebrates.”

    Allowing axolotls to disappear from the wild would carry an immeasurable risk, researchers say: There's a danger that vulnerable lab populations might be wiped out by disease, and no one knows exactly how a loss of the wild type might diminish future studies of evolution and regeneration.

    Axolotls in the lab

    Ever since the Aztecs began using axolotls for medicine and in cultural ceremonies, the odd-looking salamanders have had a special significance outside their watery homes. The use of axolotls in modern science began in the 1860s, when a French expedition collected 34 of the amphibians and shipped them to the Natural History Museum in Paris, which gave six to French zoologist Auguste Duméril. Over the past century, various labs have bred them in colonies for research.

    Among the naturalists fascinated by the axolotl's neoteny—its retention of larval characteristics such as gills into adulthood—was Stephen Jay Gould, who described the salamanders as “sexually mature tadpoles.” His book Ontogeny and Phylogeny pictured an axolotl on its cover along with a closely related tiger salamander that had fully metamorphosed and lost its gills. “The axolotl is a fascinating case of what is known as heterochrony—that is, you evolve a brand-new life history by tinkering with the timing of developmental events,” says H. Bradley Shaffer, director of the Center for Population Biology at the University of California, Davis. His research groups have worked since the 1970s on issues related to the evolution, ecology, and conservation of axolotls and tiger salamanders.

    Because of their large egg and embryo size, susceptibility to tissue grafting, and ability to regrow severed limbs and tails, “axolotls have a long history as primary amphibian models, especially in research areas involving embryonic development,” says Voss. He calls them a “re-emerging model organism” for scientists who study them with gene expression and other new tools. For example, cell and developmental biologist Elly Tanaka of the Center for Regenerative Therapies at the Dresden University of Technology in Germany says her lab was able to develop and breed transgenic axolotls, which “makes it easier to study the mysterious process of regeneration on a molecular level by driving gene expression in regenerating tissues.”

    When a salamander regrows its severed tail, it must regenerate a portion of the spinal cord and the neurons inside. “How these particular vertebrates have kept this ability to regenerate while others have lost or blocked it fascinated me,” says Tanaka, who describes the axolotl as “an interesting and important organism for studies on the evolution of vertebrate traits.” Her lab has analyzed signaling pathways that control regeneration, such as “proteins that tell a regenerating cell whether it should form an upper arm or lower arm cells.” In a paper last year in Development, her group shed light on how the axolotl's neural progenitor cells are activated to help regenerate a segment of spinal cord.

    In Kentucky, Voss's group is studying gene expression in axolotls, including differences in how brain genes function during the larval development of axolotls in contrast to closely related tiger salamanders, which metamorphose beyond the larval stage. “The data show hundreds of stable gene-expression changes that presumably evolved between these species in the last few million years.”

    Among the stem cell scientists who use axolotls in their research is Andrew Johnson of the Institute of Genetics at the University of Nottingham in the U.K., who studies the production of primordial germ cells (PGCs) in the salamander's embryos. “Axolotls are significant in that they share a mechanism that has been conserved during the evolution of mammals, in which PGCs are produced from pluripotent stem cells,” Johnson says. His group is investigating how such stem cells ignore signals that typically trigger somatic cells to differentiate.

    Salamander sanctuaries

    On the flatboat, Zambrano and a local fisherman cast a gillnet every 200 meters, drag it across the canal, and then search for salamanders. They seldom find any. “The eggs and larvae do not seem to be surviving,” he says.

    In a lab at UNAM, Zambrano and colleagues study about 40 juvenile and adult axolotls to find out more about their egg-laying habits, the most favorable breeding conditions, and their vulnerability to alien fish species, especially tilapia and carp. He attributes the axolotl decline to the rapidly increasing numbers of those predatory fish as well as changes in land use that have polluted the nearby canals.

    Shaffer points out, however, that the Xochimilco's water quality has probably improved since the 1960s and 1970s, when “many thought the native axolotls were gone.” The Mexican government began cleaning up parts of the canals and, in the late 1980s, local zoologist Virginia Graue began studying axolotl population trends and tried to increase their numbers. Zambrano did not work with Graue but expanded his own research after her death in 2004.

    Axolotl search.

    Luis Zambrano (left) and a local fisherman search for axolotls in their natural habitat, on one of Mexico City's canals.


    Noticing that the water quality varies greatly in the canal network, Zambrano has developed a model to predict where the axolotls would be able to survive. He has also outlined a plan to create sanctuaries. The first will be located in a narrow side canal in the Chinanpera area near Doll Island, on which superstitious local residents have left old dolls to scare away the ghost of a drowned girl. Invasive fish and plant species will be removed and kept away by wooden gates separating the canal from the main channel.

    A key player in international efforts to help preserve the wild-type axolotl has been zoologist Bob Johnson, the Toronto Zoo's amphibian and reptile curator. He used to support Graue's work and helped link scientists from the Mexican project with those at the Durrell Institute of Conservation and Ecology (DICE) at the University of Kent, Canterbury, in the U.K. They led a 5-year effort, supported by the Darwin Initiative, to develop a conservation program for the axolotl and the canal system. That project's funding has ended, but Johnson has since helped Zambrano and the Chapultepec Zoo get four new grants, including $19,000 from the Association of Zoos and Aquariums Conservation Endowment Fund, to help create canal sanctuaries.

    Although everyone seems to agree that the salamander's habitat needs to be preserved, some wonder if there are enough axolotls left to repopulate the canals. A veterinarian here has suggested releasing lab-raised axolotls into the canals, but Zambrano and others fear that the captive salamanders might introduce fungal and other diseases. “Even if you take rigorous precautions, diseases can still slip through the net,” says amphibian ecologist Richard A. Griffiths, who led DICE's axolotl project.

    Another fear is that introducing axolotls from ingrown lab colonies would reduce the genetic diversity of the wild type. Also, Zambrano says lab-raised axolotls likely would suffer the same fate in the canals as the wild type. “It is more effective to create sanctuaries in which the existing axolotls can survive and perhaps thrive,” he says.

    Even scientists who see only lab colonies of the salamander worry about the wild type's future. “We are concerned about the worldwide decline not only of axolotls but of many salamander species,” Tanaka says. “They represent a very important group to study in terms of evolution.”

    Neurobiologist Alejandro Sanchez Alvarado, who studies the molecular basis of regeneration at the University of Utah School of Medicine in Salt Lake City, says losing the wild axolotls would be a tragedy. “Wild-type populations provide us with a window, a record of how biological traits evolve genetically,” he says. “Who is to say that unlocking the evolutionary mystery shrouding regenerative capacities in vertebrates will not come from studying wild axolotl gene pools?”


    Philippines Plans Research Revival

    1. Dennis Normile

    The Philippines government is hoping to reinvigorate its science base by improving science education, expanding scholarship programs, and raising research spending. But will it be enough to lure back expatriate scientists?

    The Philippines government is hoping to reinvigorate its science base by improving science education, expanding scholarship programs, and raising research spending. But will it be enough to lure back expatriate scientists?

    Uncommonly good.

    This rice genetics lab in Manila is a rare hot spot of top science in the Philippines.


    Like half of his graduating class at the medical school of the University of the Philippines (UP), Manila, Edsel Salvaña grabbed his diploma and went abroad in 2001, joining an exodus that has hobbled the country's economic development. But unlike all but one other classmate who fled, Salvaña came back. After stints at the Medical College of Wisconsin in Milwaukee and at Case Western Reserve University in Cleveland, Ohio, Salvaña says, “I felt I had the skills to successfully contribute to building research efforts in the Philippines.” He returned in July and is now ramping up work on HIV and methicillin-resistant Staphylococcus aureus at the National Institutes of Health-UP Manila.

    Filipino leaders are hoping many more far-flung researchers follow in Salvaña's footsteps. After decades of neglect that resulted in a horrendous brain drain and eroding competitiveness, the Philippines government has recognized the need to reinvigorate its science base. One budding initiative is the Balik (Tagalog for “returning”) Scientist Program, which helped Salvaña find a position and provided a salary and lab start-up funds. Another boost could come from a blueprint released in October by the Congressional Commission on Science and Technology and Engineering (COMSTE) to improve science education, expand Ph.D. scholarship programs, and raise research spending. “We have been trying to get policymakers to give greater support to science and technology for years,” says COMSTE Executive Director Fortunato Dela Peña, an industrial engineer at UP Diliman. “Finally, there has been some passion building regarding this advocacy [for science].”

    The Philippines has a lot of ground to make up. Total R&D spending, at U.S. $81 million in 2007, has been stagnant for a decade and is a mere 0.14% of gross domestic product—weaker than Thailand's (0.26%) and Malaysia's (0.69%). As a result, the number of scientists and engineers conducting research in the Philippines has declined 20% since 1996 to 8800, according to the Department of Science and Technology (DOST). In comparison, despite their smaller populations, Singapore has 19,377 researchers, Thailand has 92,800, and Vietnam has 41,100. During the 1990s, a tight job market led up to half of Filipino information technologists and 60% of physicians to leave the country, according to a 2002 study by Florian Alburo, an economist at UP Diliman, and Danilo Abella, a Manila-based consultant. The duo also noted that droves of high school teachers left for the United States. Perhaps as a result, a recent study found that only one of every five high school physics teachers is qualified to teach physics. Filipino eighth graders ranked 41st in math and 42nd in science among 45 nations in the 2003 Trends in International Mathematics and Science Study.


    Returnee Edsel Salvaña.


    Filipino researchers have been brandishing such statistics at political leaders for years to make a case “that the Philippines had to start competing with other countries in the region,” says Dela Peña. One outcome was COMSTE, which the legislature tasked in February 2007 with producing a road map for restoring the country's scientific respectability. The commission's preliminary recommendations call on the government to give university research more support, establish national research institutes, develop incentives for corporate R&D, and forge closer ties between public and private sector research efforts.

    A key element of the plan is education. COMSTE's goal is to accrete a critical mass of researchers through a “massive science and engineering Ph.D. scholarship program.” “Manpower and research output from academe is the key to Philippine competitiveness,” says Reynaldo Vea, president of Mapúa Institute of Technology in Manila and head of COMSTE's education panel. COMSTE also proposes transforming several hundred secondary schools into science and math magnet schools.

    After gathering public comment and sizing up the costs, COMSTE will finalize its proposals by spring. “Our approach really builds on what previous leaders have started,” Dela Peña says. For example, legislation is in the works to enhance intellectual-property protections, and the government this year doubled DOST's budget to $110 million. The department has revamped and expanded the Balik Scientist Program, which until this year only managed to attract one or two expats a year. This year, DOST expects 50 returnees and even more in 2009. That may be a trickle of talent, but “we are confident that this program can accelerate our human resource development efforts,” says DOST Secretary Estrella Alabastro. Most returnees come on short-term visits—with transportation and per diem expenses covered by hosts—to nurture collaborations and mentor younger colleagues. A few, like Salvaña, come back full-time. Because government scholarships covered much of his education and training, he says, “I feel an obligation to give something back.” As word spreads of the improving research climate, Alabastro predicts, the trickle will become a deluge.


    Coming Soon to a Knee Near You: Cartilage Like Your Very Own

    1. Robert F. Service

    Weaving materials science and biology together, researchers are drawing closer to the elusive goal of recreating tissues that do the body's work, such as cartilage and muscle.

    Weaving materials science and biology together, researchers are drawing closer to the elusive goal of recreating tissues that do the body's work, such as cartilage and muscle

    Good as new?

    NBA star Greg Oden (left) underwent surgery last year to rebuild cartilage in his knee.


    Basketball star Greg Oden hasn't met Farshid Guilak, a biomedical engineer at Duke University in Durham, North Carolina. But as an insurance policy, Oden may want to send Guilak a few tickets each time his Portland Trailblazers play in nearby Charlotte. Oden was the first player selected in the 2007 National Basketball Association draft, yet he was sidelined his entire rookie season because of a bad right knee. After cleaning out damaged cartilage in the knee, doctors performed microfracture surgery, punching several tiny holes at the tip of the surrounding bones so that the resulting influx of blood would ferry bone marrow stem cells into the region; those cells, they hoped, would later differentiate into cartilage-producing chondrocytes and repair Oden's knee.

    Now, several games into this year's season, Oden's knee seems as solid as his monster dunks. But microfracture surgeries don't always help athletes recover. And they can't aid the millions of people with bad knees or hips due to more widespread cartilage problems, such as arthritis sufferers.

    Guilak has a potential solution: Engineer new cartilage by seeding chondrocytes onto an ultrastrong, woven polymer matrix and implant that matrix into patients. His tissue-engineered cartilage isn't ready for human trials yet, so patients like Oden should be careful for now. Still, it's getting close, and Guilak's strategy is a prime example of how materials scientists are teaming up with biologists to engineer tissues that perform mechanical work, such as cartilage, ligaments, and even heart muscle.

    Recreating such mechanically active tissues was long thought to be easier than artificially building complex organs such as the liver and pancreas. (See special section on how organs naturally form, p. 1489.) But imitating the mechanical feats performed by natural tissue is a tall order. For example, the cartilage in your body's joints can withstand 12 megapascals of pressure—more than 10 times the amount generated if you hang from a ledge by a single fingernail. Researchers have already made significant progress in building new bone that's as strong as the natural stuff (Science, 1 September 2000, p. 1498). Now, they are extending that success to softer mechanically active tissues by learning to mimic many of their key attributes. “It's a breakthrough time in this field, where we are seeing several biomimetic capabilities coming together,” says Guilak.

    Next best thing.

    A woven scaffold made of a biodegradable polymer helps seed cells that can produce new cartilage.


    Crunched cartilage

    Off the basketball court, the most common type of cartilage damage is the widespread loss of tissue that's a hallmark of many forms of arthritis. According to the Arthritis Foundation, arthritis costs the U.S. economy alone $128 billion per year in medical bills and indirect expenses, including lost wages and productivity. In arthritis patients, the healthy cartilage that lubricates and cushions the impact between adjoining bones breaks down over time. Bones then rub directly against one another, causing pain and loss of movement in the joint. Cartilage contains no nerves. So by the time patients feel pain, significant amounts of cartilage may already be gone.

    When the loss is slight, as was the case with Oden, doctors use microfracture surgery to trigger new cartilage growth, even though replacement cartilage is typically weaker than the original. Other treatments include transplanting cartilage from elsewhere in the patient's body into the afflicted area, as well as harvesting a person's chondrocytes from a region of healthy cartilage, amplifying them in a lab, and reinjecting them into a patient's joint. But none of these efforts produce cartilage that's as strong as the original. And when cartilage loss is extensive, doctors can do little other than completely replace the joints with metal and plastic prostheses. That can offer immediate pain relief, but replacement joints often wear out after only a decade and can typically be replaced only once, due to accumulated damage to the patient's bones, says Gerard Ateshian, a biomedical engineer at Columbia University.

    As an alternative, cell-free synthetic cartilage has made some progress. In select cases, doctors can inject a polymer gel into joints to help ease symptoms. But such procedures often offer only temporary relief because the gel breaks down. Prospects are a bit better for gels used to replace damaged disks between vertebrae in the spine; those gels can be injected and contained within the thin, fibrous sac that houses the cartilagelike material of a normal disk. Michele Marcolongo and colleagues at Drexel University in Philadelphia, Pennsylvania, for example, have made gels from a copolymer of polyvinyl alcohol and polyvinyl pyrrolidone. The gels are tough and resilient, capable of withstanding up to 10 million cycles of compression and release in lab studies. Marcolongo's technology has been picked up by the medical devices company Synthes Spine, whose preclinical studies on animals suggest that the treatment seems to “completely restore mechanics,” Marcolongo says.

    Fully synthetic gels have had less success in the knee and other less well-confined spaces. The arrangement of these joints requires that the cushioning material in the middle be able to withstand as much as 10 times a person's weight. Gels compressed with that much force typically squish out to the sides, like a spoon pressing down on a slab of Jell-O. By contrast, collagen fibers in natural cartilage make it extremely stiff so that it resists squishing outward under an applied force, Ateshian says.

    Stronger scaffolds

    To craft such strong tissue, researchers have focused on coaxing the body to grow its own additional cartilage cells on a synthetic template, rather than trying to recreate cartilage from scratch. Researchers have seeded cartilage-producing chondrocytes onto synthetic scaffolds in vitro for decades in hopes that this would cause the cells to generate new cartilage with the same impressive properties as the native version. But the results have almost always been disappointing. Chondrocytes do grow and put out a mixture of collagen and charged compounds called proteoglycans. But the resulting cartilage winds up far weaker.

    Ateshian has recently made tougher cartilage by applying a little force of his own. Growing cartilage can sense mechanical stress and responds by becoming stronger, akin to the way that weight training helps build strong bones. Ateshian applied this principle back in 2000, when his team reported seeding a culture of chondrocytes onto a synthetic hydrogel and compressing the gel in a chamber. The resulting new cartilage was five times stronger than that created without mechanical loading. Recently, the team has boosted that strength up to about 20% of that of native cartilage by cycling the compression on and off and adding a cocktail of growth factors.

    In a variation on this theme, Rocky Tuan, a tissue engineer at the National Institute of Arthritis and Musculoskeletal and Skin Diseases in Bethesda, Maryland, is also putting weight on tissues and adding growth factors. But Tuan and his colleagues deposit their cells atop fibers of a biodegradable polymer called poly(α-hydroxy ester). Tuan first learned to spin the fibers a decade ago with an apparatus akin to those that spin cotton candy from sugar. His lab has since perfected techniques to align the fibers to better control cartilage growth and resist compression. Tuan says his team's artificial cartilage now also has about 20% of the strength of native cartilage. “We would like to get to 40% to 50%,” Tuan says. He adds that most clinicians believe that will be good enough to restore mobility for many patients. In a paper in press at the Journal of Tissue Engineering and Regenerative Medicine, Tuan and his colleagues report that after implanting their synthetic cartilage into pigs' hip joints, the material seemed to integrate well with the native cartilage; the animals appeared to walk normally as well.

    Mending broken hearts.

    A polymer scaffold (top and above in blue) causes heart muscle cells (above in green) to align and contract in a preferred direction.


    Tuan's nanofiber scaffolds, however, have very small pores, making it difficult for chondrocytes to penetrate and churn out new cartilage. Guilak's team has made progress with a scaffold that leaves plenty of room for the cells. He, Franklin Moutos of Duke, and Lisa Freed of the Massachusetts Institute of Technology (MIT) in Cambridge have created a novel three-dimensional weaving technique for building high-strength scaffolds. The trio wove their scaffold with a yarn made from a biodegradable polymer called polyglycolic acid (PGA) and seeded it with chondrocytes, they reported in Nature Materials last year. The woven fabric gave the scaffold compressive, tensile, and sheer strength on the same order of magnitude as native cartilage. That's a “major advance” and “an exciting opportunity for tissue engineers,” Ateshian wrote in a commentary at the time.

    Guilak's engineered cartilage still had some drawbacks. The PGA used to weave the scaffold degraded in about 2 weeks, too quickly for the seeded chondrocytes to churn out the collagen and proteoglycans needed to rebuild strong cartilage. Guilak's team has since turned to another polymer known as poly(ε-caprolactone) that degrades more slowly. Cytex Therapeutics, a biotech start-up in Durham, North Carolina, is now carrying out preclinical animal studies with the artificial cartilage and hopes to launch human trials in 2010.

    Freed and her MIT colleagues have also been working to extend their success with patterned scaffolds to other tissues as well. Freed and postdoc George Engelmayr Jr. recently led a team that created artificial heart-muscle tissue from a honeycomb-shaped scaffold that flexes like an accordion. Cells in heart muscle, Freed explains, are aligned in specific directions to coordinate how the muscle flexes. Most biomaterial scaffolds, however, can't reproduce this alignment.

    To do so, the team used a computer-controlled excimer laser to cut a precise pattern of holes and grooves in successive layers of a rubberlike degradable polymer scaffold. They then seeded the scaffold with neonatal rat heart cells. Not only did the cells grow in a preferred orientation, but when prompted by an electric field, they also contracted in the preferred direction, the team reports in the December issue of Nature Materials.

    The group is working to optimize the pores in the structure and to build a microfluidic perfusion chamber to feed nutrients into the cells. Ultimately, Freed adds, the hope is that the novel scaffolds can be used to create artificial heart-muscle patches to repair small sections of diseased heart tissue. Guilak says he's impressed with Freed's team's ability to pattern cells: “You could apply this to a number of tissues, including tendons and ligaments.” Tissue engineers are hoping not only that this will happen but also that the results will begin to alleviate the suffering of arthritis patients and perhaps even keep a few basketball stars on the court.