News this Week

Science  31 Aug 2012:
Vol. 337, Issue 6098, pp. 1024
  1. Around the World

    1 - Tehran
    Options Narrow for Iranian Women
    2 - Washington, D.C.
    Legal Win for Stem Cell Research
    3 - Bethesda, Maryland
    NIH's Millionaires to Get Extra Scrutiny
    4 - Toronto, Canada
    Canada's Cash Controversy
    5 - Princeton, New Jersey
    Promising Hepatitis C Drug Scuttled
    6 - Beijing
    Cheetah Fossil a Fake
    7 - Canada
    Arctic Research Station Gets Funded

    Tehran

    Options Narrow for Iranian Women

    An Iranian woman waits to vote in the 2005 presidental election.

    CREDIT: AP PHOTO/HASAN SARBAKHSHIAN

    Iran's science ministry has forbidden women to study dozens of subjects at 36 universities, according to reports by state-run media. The decree marks a significant erosion of gender-equality measures introduced by former President Mohammad Khatami a decade ago. “Gender discrimination has been reintroduced,” says a scholar in Tehran who requested anonymity.

    The move is part of a months-long effort to segregate students by gender in the wake of anti-government protests in 2009. Subjects now off limits to female students include nuclear physics, petroleum engineering, and English literature. The restrictions came to light earlier this month. Last week, state media noted the latest salvo in the Iran government's campaign: the establishment of 12 women-only hospitals at medical universities.

    “There is a lot of fight-back,” including picketing on campuses, says the Iranian scholar. But the female students have not yet recaptured any lost ground.

    Washington, D.C.

    Legal Win for Stem Cell Research

    Neurons derived from human embryonic stem cells.

    CREDIT: RUSSO, PLOS BIOLOGY 3, 7 (12 JULY 2005)

    A three-judge panel of a U.S. appeals court ruled last week that federally funded research on human embryonic stem cells (hESCs) is legal, bringing closer to an end a court battle that has threatened to block hESC research funded by the National Institutes of Health (NIH).

    The suit, Sherley v. Sebelius, was filed 3 years ago by two scientists who study adult stem cells. They argued that new NIH guidelines easing limits on hESC research violated a 16-year-old law banning federal funds for research in which human embryos are destroyed. On 24 August, Chief Judge David Sentelle of the U.S Court of Appeals for the D.C. Circuit upheld a lower court's ruling, stating that NIH “had reasonably interpreted” the law to allow for federal funding of hESC studies because research on hESCs and their derivation are separate.

    While the other two judges concurred, they did so for different reasons, increasing the chance that the plaintiffs will successfully petition for a new review by the full court, legal experts say. An attorney for the plaintiffs said they are more likely to appeal to the U.S. Supreme Court.

    http://scim.ag/stem_cell_law

    Bethesda, Maryland

    NIH's Millionaires to Get Extra Scrutiny

    National Institutes of Health.

    CREDIT: NIH

    Researchers with more than $1 million a year in grants will get extra scrutiny from the U.S. National Institutes of Health (NIH) under a new policy.

    The plan is one of several ideas NIH has floated to squeeze more research grants from its flat budget. Applications from principal investigators (PIs) with at least $1 million a year in direct research funding will get an extra review from the funding institute's scientific council to make sure the research is “both highly promising and distinct from” the PI's other projects, NIH announced on 20 August.

    About 89 grants will meet the cutoff for review at September's council meetings. That's less than 1% of all proposals going to the councils, NIH estimates. And because the policy is not a cap, it's unclear how much money it will ultimately free up.

    Howard Garrison of the Federation of American Societies for Experimental Biology says the policy is important anyway. “It's not necessarily going to solve all our problems. But people felt it was an appropriate step,” Garrison says.

    http://scim.ag/NIH_grants

    Toronto, Canada

    Canada's Cash Controversy

    On 20 August, the Bank of Canada apologized for expunging an Asian-looking scientist from a new $100 banknote after some Canadians objected to the figure.

    The kerfuffle over the image began several years ago when focus groups reviewed the proposed design for a bill highlighting Canada's contributions to biomedical science. Some group members complained that “Asian should not be the only ethnicity represented” and that the image “stereotype[d] … Asians [as] excelling in technology and/or the sciences,” The Vancouver Sun reported. The bank redrew the image to appear more Caucasian, a move that has ruffled feathers.

    The new plasticized banknotes, which went into circulation this year, are more secure, cheaper, and greener than existing bills. The bank's governor said the bank will not reinstate the original image on the bill, but will review the design process for new currency in light of the ensuing public outcry. http://scim.ag/CAcash

    Princeton, New Jersey

    Promising Hepatitis C Drug Scuttled

    Electron micrograph of HCV.

    CREDIT: COURTESY OF THE CENTER FOR THE STUDY OF HEPATITIS C, THE ROCKEFELLER UNIVERSITY/CHARLIE RICE

    Bristol-Myers Squibb announced on 23 August that it had pulled the plug on development of a promising drug that directly attacks the hepatitis C virus (HCV). HCV infects an estimated 160 million people worldwide and causes liver damage. Known as BMS-986094, the drug showed serious toxic effects when one patient in a clinical trial of the compound died from heart failure and eight others were hospitalized for heart and kidney toxicity. The drug, which was tested on about 250 people, inhibits a nucleotide polymerase that HCV needs to copy itself.

    Meanwhile, the U.S. Food and Drug Administration put another nucleotide polymerase inhibitor made by Idenix of Cambridge, Massachusetts, on “partial clinical hold” to review safety data. A third drug in this class, GS-7977, made by Gilead Sciences of Foster City, California, has moved furthest along in the development pipeline, and has not raised significant safety concerns. “Developing a drug is like Internet dating,” says Tracy Swan, who directs the hepatitis project at the Treatment Action Group, an advocacy group in New York City. “The less you know the better it looks.”

    Beijing

    Cheetah Fossil a Fake

    An embarrassing saga for paleontologists and a top science journal has ended. The Proceedings of the National Academy of Sciences (PNAS) posted a retraction online on 20 August acknowledging that a cheetah skull—described in a January 2009 report as “the most primitive cheetah known to date”—was a false composite of much older bones.

    In the original paper, Ji H. Mazák of the Shanghai Science and Technology Museum and Per Christiansen, then of the Zoological Museum in Copenhagen, described the skull's “unique combination of primitive and derived traits.” Only days later, Deng Tao, an early mammals expert at the Institute of Vertebrate Paleontology and Paleoanthropology in Beijing, wrote a letter to PNAS calling the cheetah skull a “fossil forgery.” PNAS declined to publish Deng's letter, and Mazák refused to give Deng access to the skull (Science, 24 December 2010, p. 1740). Mazák relented last May, allowing Deng to examine the specimen. “I saw that the fossil was very seriously forged,” Deng says. Mazák, he says, concurred and signed the retraction. Christiansen, now chief zoologist at Aalborg Zoo in Denmark, told Retraction Watch that he “had no idea about any of this” and that PNAS did not contact him about the retraction.

    Canada

    Arctic Research Station Gets Funded

    Last week, Canada announced that it has ear-marked more than CAD $140 million (about US $141 million) for a new research station in the High Arctic, with an additional CAD $46 million set aside for the station's “science and technology program.” The announcement comes only months after another Canadian research station, the Polar Environment Atmospheric Research Laboratory (PEARL), responsible for monitoring polar atmospheric conditions, was forced to cease year-round operations because of funding cuts. The new facility is 1300 kilometers south of PEARL and cannot adopt its role monitoring changes in air quality, climate, or the ozone. “No one in the [scientific] community has a clue what this [new facility] is going to be used for,” says climate scientist Andrew Weaver of University of Victoria in Canada. The announcement by Canada's Prime Minister Stephen Harper “is all about sovereignty, gas, and oil exploration, and has absolutely nothing to do with science,” he adds. Construction on the research station located in Cambridge Bay in northwest Canada will start next year. It is scheduled for completion in 2017.

  2. Random Sample

    Noted

    After landing on Mars, taking its first steps, and testing its rock-zapping laser, on 28 August the intrepid Curiosity rover also burst into song. Rapper will.i.am wrote the song, titled “Reach for the Stars.” NASA arranged the interplanetary broadcast to correspond with an event about Mars research aimed at grades K–12.

    Winking at the Moon

    CREDIT: NASA

    Astronaut Neil Armstrong, the first person to walk on the moon, died last Saturday at the age of 82. On 20 July 1969, Armstrong and Apollo 11 spacecraft co-pilot Edwin “Buzz” Aldrin took mankind's first steps on another heavenly object. The mission was Armstrong's third, and last, spaceflight. He left NASA in 1971 and became a professor of aeronautical engineering at the University of Cincinnati in Ohio, where he taught for almost a decade. He spent the rest of his career serving on the board of several large high-tech companies before retiring to a farm in his home state of Ohio. “The next time you walk outside on a clear night and see the moon smiling down at you,” his family said in a statement Saturday, “think of Neil Armstrong and give him a wink.”

    Oldest Arthropods in Amber

    CREDIT: UNIVERSITY OF PADOVA/S. CASTELLI

    Roughly 230 million years ago, two mites and a midge got stuck in oozing resin from a now-extinct species of conifer tree in the mountains of northeastern Italy. The insects have now earned the distinction of being the oldest arthropods—invertebrates that include insects, arachnids, and crustaceans—ever found preserved in amber. Arthropods have scuttled over Earth's surface for more than 400 million years, but prior to this discovery the oldest specimens in amber were 130 million years old.

    The three amber-bound arthropods were among roughly 70,000 bits of amber (pictured) excavated from an outcrop in the Italian Dolomite Alps. Unlike the midge, the mites are intact, which allowed the team to identify two new species of mites: Triasacarus fedelei and Ampezzoa triassica. In their study, published on 27 August in the Proceedings of the National Academy of Sciences, the researchers report that the mites are the oldest known ancestors of the Eriophyoidea group of mites, which today includes at least 3500 species.

    They Said It

    “The sea-ice death spiral, coming during one of the warmest summers in American history, is just one more clear sign of the deepening climate crisis that we ignore at our own peril.”

    —Shaye Wolf, climate science director at the Center for Biological Diversity's Climate Law Institute in San Francisco, California, referring to record low levels of sea ice in the Arctic measured on 26 August.

    By the Numbers

    $78.6 million Cost of a new trial by the National Heart, Lung and Blood Institute, part of the National Institutes of Health, to test whether an anti-inflammatory medication prevents cardiovascular disease.

    964 Number of measles cases in England and Wales in the first 6 months of 2012, up from 497 in the same period last year.

    58% Percentage of likely American voters who think that Indian and Chinese schools are catching up to, or have surpassed, K–12 schools in America, according to a survey of 1227 adults released on 21 August by nonprofit organization The Center for the Next Generation.

    Sparks Fly Over Tesla Museum

    CREDIT: TESLA WARDENCLYFFE PROJECT ARCHIVES

    Nikola Tesla is credited with inventing wireless transmission, AC power, fluorescent lighting, and other essentials of modern life—yet in the United States, he is still largely unsung. Now, an Internet fundraiser has raised more than $1 million to build a museum to honor the eccentric Serbian-American scientist.

    For nearly 2 decades, organizers of the Tesla Science Center at Wardenclyffe—a nonprofit organization seeking to promote Tesla's contributions to science—have been eyeing the approximately 6-hectare site in Shoreham, New York, where Tesla (left) owned a lab from 1901 to 1915. A futuristic building with a transmission tower (right), the Wardenclyffe lab was supposed to transmit radio and power wirelessly to the world, but it was never completed. Ownership of the site went to the Agfa Corp., which recently decided to sell. The Tesla Science Center pounced on the purchase, says the center's president, Jane Alcorn. “We realized the opportunity was now.”

    Fundraising for the museum took off when Alcorn got an e-mail from Matthew Inman, creator of the Internet cartoon The Oatmeal (http://theoatmeal.com). Inman's popular cartoon “Operation Let's Build a Goddamn Tesla Museum” raised the required $850,000—which will be matched by New York state—to secure the Wardenclyffe site in less than a week. The 22,000 donors included founders of the electric car company Tesla Motors.

    Now that it has purchased the land, the Tesla Science Center is raising money to build the museum itself (http://igg.me/p/204900). “Tesla had extravagant dreams, and a wonderfully out-of-the-box kind of imagination,” Alcorn says. “We want it to be dramatic and inspiring.”

    ScienceLive

    Join us on Thursday, 6 September, at 3 p.m. EDT for a live chat on head injury and trauma in soldiers and athletes. http://scim.ag/science-live

  3. Astrobiology

    In the Hunt for the Red Planet's Dirtiest Secret

    1. Richard A. Kerr

    More obstacles to Curiosity rover's search for the organic remains of martian life are turning up, complicating an already daunting task.

    On to organics?

    By far the most promising site for Curiosity rover's search for life's organic matter is the base of 5-kilometer-high Mount Sharp.

    CREDIT: NASA/JPL-CALTECH/MSSS/DAMIEN BOUIC, HTTP://WWW.DB-PRODS.NET/MARSROVERSIMAGES

    Discovering the organic remains of life can be dirt-simple, at least on Earth. Kneel in any reasonably productive garden and your pants will carry the dark stains—organic matter—of long-dead and decomposed tomatoes, basil, and earthworms.

    Finding signs of life that thrived eons ago is an entirely different matter. Just ask geologist John Grotzinger. After 20 years of fieldwork roaming across the Precambrian rock of Namibia, he had found only three new fossil deposits. “It's actually hard to find fossils,” Grotzinger says, “and that's on Earth. This is really just hard to do.”

    But now as project scientist on the Curiosity rover mission, Grotzinger and his 400-strong science team are taking on a far greater challenge: searching 3-billion-year-old rock at a single spot on an alien planet for the organic remains—molecular fossils, if you will—of life. Finding such organic matter on Mars “is just going to be very, very hard to do,” Grotzinger says.

    The complicator.

    The Phoenix lander discovered martian perchlorate that, once cosmic rays decompose it, destroys organic matter.

    CREDIT: NASA/JPL-CALTECH/UNIVERSITY OF ARIZONA

    And as Curiosity cruised toward Mars and a safe landing on 6 August (EDT), researchers were recognizing yet more ways that Mars could be destroying organic evidence of any past life. Megajoule cosmic rays blast organic molecules to bits, and a chemically reactive brew in martian soil probably chews up organic matter in a few millennia, never mind eons. Given the dearth of studies of organic matter's fate under martian conditions, Curiosity's chances of success are anyone's guess.

    0 for 3, so far

    Three times, NASA has sent spacecraft that could detect organic matter to the surface of Mars. And three times, martian soil has yielded no organics. All three of those landers—Viking landers 1 and 2 in 1976 and the Phoenix lander in 2008—carried analytical systems with the same basic design as Curiosity's. A soil sample is heated to hundreds of degrees, driving off volatile organics or breaking down nonvolatile organics into fragments that can also be driven off. In Viking, the volatilized organics were separated from one another as they passed through a gas chromatograph. In all three, a mass spectrometer then identified each organic compound by its mass.

    But even though the Viking landers were sensitive enough to detect organics in concentrations of a few parts per billion, they found nothing more than trace amounts of two small chlorine-containing hydrocarbons. Those were identified as contaminants. Phoenix produced some carbon dioxide, but team members concluded that it probably came from the breakdown of inorganic carbonate, not organics.

    The nondetection of martian organics was quite a puzzler. Everyone knew that something like 1000 tons of organic matter gets dumped on Mars every year as organic-rich cosmic dust—debris from comets and asteroids—sifts to the surface. Left to accumulate, that much organic matter would lead to soil concentrations of tens of thousands of parts per million, not sub-part-per-billion. The missing organic matter prompted much talk of a “superoxidizer” in martian soil, a chemical that could destroy organics by adding oxygen to them and eventually converting them entirely to carbon dioxide.

    The Viking landers were not designed to measure oxidizers, but plenty of candidates were put forward. They included hydrogen peroxide produced by solar ultraviolet hitting the atmosphere, nanophase iron in minerals, and oxidizers produced when whirling dust devils electrically charge up the atmosphere, among others.

    Looking bleak

    Thirty years later, Phoenix finally detected a bona fide oxidizer in martian soil: perchlorate salts likely produced in the atmosphere. Perchlorate—a combination of a chlorine atom and four oxygen atoms that can pair with a metallic atom like magnesium—won't oxidize much of anything if left to itself at martian temperatures. But hit it with enough energy and it can do plenty of damage.

    One way to energize perchlorates would be to irradiate them. Perchlorates on Mars are continually bombarded by galactic cosmic rays that can decompose them into potent oxidizers like hypochlorite (the active component of household bleach). Geochemist Richard Quinn of NASA's Ames Research Center in Mountain View, California, and his colleagues created something like martian irradiation conditions in the lab by bombarding magnesium perchlorate with x-rays that, like cosmic rays, can decompose perchlorates. As they reported at the 2011 Lunar and Planetary Science Conference, Mars-like irradiation produced four or five chlorine-containing breakdown products, including hypochlorite.

    By including irradiated perchlorates in lab reruns of two Viking lander experiments, Quinn and his colleagues showed that perchlorates also likely yield strong oxidizers on Mars. They found that irradiated perchlorate released oxygen gas when moistened, just as soil samples did in Viking's Gas Exchange experiment. And when irradiated perchlorate was moistened with a solution containing the organic compound formate, carbon dioxide containing the formate's carbon was generated, just as happened in Viking's Labeled Release experiment.

    But degraded perchlorate is not the only emerging threat to martian soil organics. Cosmic rays themselves destroy organic matter. So planetary scientist Alexander Pavlov of NASA's Goddard Space Flight Center in Greenbelt, Maryland, and his colleagues calculated as best they could how fast cosmic rays might be destroying organics on Mars. “The problem is that very little experimental work has been done” on how quickly cosmic rays can degrade organics, Pavlov says. But they took one experimentally determined destruction rate for amino acids reported in the literature and combined it with the flux of cosmic rays expected to pass unimpeded through the vanishingly thin martian atmosphere and penetrate a meter or two into surface rock.

    As the group reported in a Geophysical Research Letters paper published on 7 July, the prospects are not good for finding big, complex organic molecules—the hallmark of once-living organisms—near the surface. Cosmic-ray irradiation “is a problem if you're going for something billions of years old only to [a depth of] 10 centimeters,” Pavlov says—about the depth soil samples can be scooped. Small organics have a longer lifetime, he explains, because they present a smaller target for cosmic rays, “but they're not going to be definitive evidence for life.” And that's a conservative prognosis. Destruction rates in martian soil are likely to be faster—possibly 100 times faster—than the laboratory rates determined in the absence of minerals, the group writes. “That will pose a serious challenge for organic detection.”

    And then there is the ultraviolet radiation. Because the atmosphere of Mars lacks protective ozone, the sun's ultraviolet strikes the surface at full force. Although it penetrates rock less than a millimeter, that is enough to destroy the organic matter of incoming cosmic dust, according to a study published on 17 August in two papers in the Journal of Geophysical Research—Planets.

    Lab in a box.

    With three instruments connected by 600 meters of wiring, Curiosity's microwave-oven-size SAM can analyze the chemical and isotopic makeup of martian soil, rock, and atmosphere.

    CREDIT: NASA-GSFC

    Planetary scientists John Moores of the University of Western Ontario in London, Canada; Andrew Schuerger of the University of Florida, Gainesville (working at the Kennedy Space Center); and colleagues exposed finely ground, organics-rich meteorite to martian surface conditions, including the ultraviolet radiation. They then applied their observed rate of decomposition to the expected properties of the cosmic dust settling onto Mars. They calculate that ultraviolet radiation would destroy half of the cosmic dust's organic matter in about a millennium and in several millennia it would all be gone.

    Organic hide and seek

    With decomposed perchlorates, cosmic rays, and ultraviolet radiation ganging up on martian organic matter, Curiosity's chances of finding it when it scoops up its first soil samples are looking slim. And “if we find [soil] organics, it almost certainly will have nothing to do with life,” says astrobiologist Christopher McKay of NASA Ames. The most likely organics in soils would be those of cosmic dust because they are continually resupplied, so “detecting organics is not detecting life,” he says.

    To maximize the chance of finding ancient life's molecular remains intact, Curiosity will have to go for solid rock, and not just any rock, Pavlov says. Unlike its predecessors, Curiosity carries a drill, which can retrieve 10-centimeter-long cores from solid rock. But centimeters of protection won't be enough, Pavlov says: “Our paper calls for being very smart about where you sample.” Rather than drilling a geologically enticing outcrop that may have been irradiated by cosmic rays for eons, Pavlov argues for sampling rock exposed only in the geologically recent past, say by being recently excavated by a small meteorite impact.

    To up the odds even more, Curiosity has been sent to Gale crater. Grotzinger would be surprised if the enclosed bowl of Gale, one of the lowest spots on the planet, did not hold a lake in ancient times. On Earth, lakes are prime spots for both producing and preserving organic matter. And Curiosity's target rocks at the base of Gale's central mound are layered with clays, water-altered minerals that can protect organic matter from chemical degradation, especially if quickly buried by more sediment.

    And then there is SAM. The Sample Analysis at Mars instrument package will analyze soil and rock samples collected by Curiosity. Although it includes the same basic components as Viking landers and Phoenix, SAM “is a powerful suite of instruments,” says McKay, who is on the SAM team. For example, SAM can chemically process samples to prevent perchlorates from destroying organics during the analysis, as McKay suspects happened during Viking. “We have a lot more flexibility and adaptability to explore,” he says. He and the rest of Curiosity's 400 are going to need it.

  4. Immunology

    The New View of Complement

    1. Mitch Leslie

    This cascade of immune proteins has more diverse roles, and can cause more problems, in the body than once thought

    Stealing vision.

    Drusen, the small, milky blotches on the retina of a patient with age-related macular degeneration, carry proteins from the complement system.

    CREDIT: NATIONAL EYE INSTITUTE, NATIONAL INSTITUTES OF HEALTH

    If you visited immunologist William Robinson's lab at the Stanford University School of Medicine in Palo Alto, California, a couple of years ago, you might have found his postdoc Qian Wang operating on the knees of mice, performing the same surgery that many athletes undergo to repair a torn meniscus. No, the animals hadn't hurt themselves by running too vigorously on their wheels. Instead, the researchers were testing an unorthodox hypothesis about the cause of osteoarthritis (OA), the painful and sometimes crippling joint degeneration that strikes many of us as we age.

    The standard explanation for OA attributes it to the gradual erosion of our joints over decades, but there have long been hints that something else is involved. The autoimmune disease rheumatoid arthritis, another condition that impairs the body's joints, stems from inflammation triggered by the immune system, and the joints of OA patients often show milder inflammation. Researchers haven't been sure, however, whether inflammation drives the damage of OA or is a byproduct of it.

    To find out, Robinson's team began operating on multiple strains of genetically engineered mice that lacked various inflammation-promoting genes, carving away some of their knee cartilage because that typically induces OA. (Athletes who have meniscus surgery frequently develop the arthritis.) The researchers got a jolt when they performed the surgery on mice lacking genes for the complement system, a cadre of immune proteins that researchers didn't think was a factor in OA. Rodents lacking either of two complement proteins incurred about 50% less knee damage than did control animals. And as the team reported last December in Nature Medicine, mice missing a complement-inhibiting protein showed more severe erosion. A role for complement in OA is an intellectual leap. “Everyone thinks that OA is simple wear and tear in the joint,” Robinson says. “Complement may play a crucial role in the breakdown of cartilage and destruction of the joint in OA.”

    Arthritis researchers aren't the only scientists recently taken aback by new insights into the complement system. Again and again, it has confounded expectations, proving to be more versatile and powerful than anyone thought. Not that long ago, most researchers agreed that, as its name suggests, complement was a mere helper for immune cells. But then further research demonstrated that the system is one of our most important protections against pathogens, killing invaders before other immune defenses have a chance to mobilize.

    Even more unexpected, some researchers say, is the increasing evidence that complement components perform functions outside the immune system. Complement takes part in the body's growth and maintenance, for example. Recent work suggests it guides development of the brain and skeleton and spurs damaged organs to repair themselves. “The term ‘complement’ is a misnomer,” says immunologist John Lambris of the University of Pennsylvania's Perelman School of Medicine.

    But if complement does a lot of good in the body, it can also do us harm. “It's an essential component of normal physiology and pathophysiology,” says Lambris, who notes that researchers have implicated the system in more than 30 illnesses. The list includes diseases and conditions known to have an immune connection—such as sepsis, rheumatoid arthritis, and organ transplant rejection—and ones that scientists didn't consider immune system diseases, such as OA and age-related macular degeneration (AMD), the leading cause of blindness for older people in the developed world. The recent work “redefines these degenerative diseases as having a significant immune component and opens up new avenues for treatment,” Robinson says.

    Already, two drugs have been approved for complement-related diseases, and several other compounds targeting proteins in the cascade are in clinical trials for a variety of conditions. “That's pretty remarkable, and it's just the beginning,” says immunologist John Atkinson of Washington University School of Medicine in St. Louis, who has studied complement for more than 40 years.

    Standing guard

    Complement belongs to the innate arm of the immune system. Unlike the adaptive immune system that includes B and T cells, the innate arm doesn't for the most part customize its defenses for specific pathogens. Complement was one of the first immune defenses recognized; at the end of the 19th century, researchers discovered that blood serum contained a bacterium-killing component in addition to antibodies. Complement was also one of the earliest defenses to evolve: Only vertebrates can muster B cells and T cells, but even sponges boast complement proteins, Lambris notes.

    Complement usually leads the body's counterattack against bacteria. In contrast to the adaptive immune system, which can take days or even weeks to reach peak performance, complement is always ready for action, and it dispatches invaders swiftly. “It's an amazing first responder,” Atkinson says. “It can lyse a bug in 30 seconds.”

    Lines of attack.

    This simplified diagram traces the main pathways of the complement cascade.

    CREDIT: B. STRAUCH/SCIENCE

    A sign of complement's importance to our survival is that it accounts for about 4% of the proteins in our blood. Among the more than 30 types of complement proteins are danger detectors, activators that switch on other proteins, and inhibitors that curb self-directed attacks. They fall into three interconnected pathways (see figure). Those proteins on the lookout for potential threats are constantly checking the blood and scanning the surfaces of our cells. The complement system has several options once it detects a pathogen or other danger. In the most dramatic response, the complement component C5b and other proteins convene to form a membrane attack complex, which lands on the surface of a microbe and pierces its membrane.

    “Everyone thinks that OA [osteoarthritis] is simple wear and tear in the joint. … Complement may play a crucial role in the breakdown of cartilage and destruction of the joint in OA.”

    —WILLIAM ROBINSON, STANFORD UNIVERSITY SCHOOL OF MEDICINE

    CREDIT: MARK ESTES
    Breaking down.

    The knee of a control mouse shows more arthritic erosion (left, arrows) than one of a mouse that lacks the complement protein C5 (right).

    CREDIT: Q. WANG ET AL., NATURE MEDICINE 17, 12 (6 NOVEMBER 2011) © 2011 NATURE PUBLISHING GROUP

    Stimulating complement can also spur defensive cells such as macrophages to eat an intruder and crank up inflammation, another protective measure. Complement is so good at its job, says immunochemist Robert Sim of the University of Oxford in the United Kingdom, that you usually aren't aware it's working; it kills off invading bacteria before they have the opportunity to make you sick.

    Another of complement's crucial roles involves searching out dying body cells and molecular junk. Complement proteins tag but don't remove the refuse—they hail a macrophage or other cell to clean up—and autoimmune diseases such as lupus may result from the failure of complement to help eliminate this debris.

    Growth and regrowth

    Keeping the body safe is complement's traditional job, so tidying up potentially dangerous cellular flotsam isn't out of character. But recent revelations that complement helps steer normal development and fosters the repair and regeneration of damaged tissues have stretched our view of its contributions. Complement's role in development is “the most striking” of its newly uncovered abilities, Sim says.

    Several years ago, for example, a study led by neuroscientists Ben Barres of Stanford and Beth Stevens, now at Harvard Medical School in Boston, suggested that complement helps cut away unnecessary synapses during brain formation in young mice (Science, 14 December 2007, p. 1710). Earlier this year in Neuron, Stevens, Barres, and colleagues revealed how, showing that the complement protein C3 helps spur microglia, immune cells in the brain, to eat the unwanted connections.

    Other studies point to developmental roles outside the nervous system. Last year, a multinational team of researchers reported that mutations in two complement genes were behind 3MC syndrome. Because children with this rare condition have facial deformities as well as learning disabilities, the finding indicates that complement helps shape the skeleton.

    Another aspect of complement's softer side is its role in the restoration of damaged tissues and organs. Unlike most other organs, the liver can regenerate after an injury. The liver also manufactures most of the body's complement proteins—and the two capabilities seem to be related. “We have found that complement-deficient mice have impaired liver regeneration,” Lambris says. An injury, such as one caused by a liver-damaging chemical, spurs production of the complement proteins C3a and C5a. The molecular details of how these proteins prompt the liver to refurbish itself remain unclear, Lambris says. But 3 years ago, he and his colleagues discovered that the proteins help keep dividing liver cells alive by activating a protective pathway.

    “The term ‘complement’ is a misnomer. It's an essential component of normal physiology and pathophysiology.”

    —JOHN LAMBRIS, UNIVERSITY OF PENNSYLVANIA

    CREDIT: COURTESY OF PERELMAN SCHOOL OF MEDICINE, UNIVERSITY OF PENNSYLVANIA

    The price of vigilance

    Then there's the dark side of the complement system. “You need it, and if you don't have it you either get infections or you develop autoimmunity,” Atkinson says. “But you don't want to turn it on a healthy cell.”

    Researchers are uncovering more and more instances in which that occurs. For example, complement attacks might take years off the working lives of transplanted organs. The cascade triggers much of the damage from so-called ischemia-reperfusion injuries, which occur after blood flow to a tissue or organ is temporarily cut off—such as by a blood clot or removal of the organ from a donor's body in preparation for transplantation. The two complement proteins C5a and C5b are the main culprits. C5a fires up damaging inflammation by stimulating immune cells known as neutrophils. Meanwhile, C5b and other proteins form membrane attack complexes that kill cells in the donor organ.

    The effects of complement typically aren't severe enough to prevent a newly transplanted organ from working, says transplant immunologist Steven Sacks of the MRC Centre for Transplantation at King's College London. But all transplants eventually fail, and complement could hasten that process. “The question is why a 40-year-old organ doesn't last another 30 years,” Sacks says.

    He and his colleagues have developed a possible way to reduce complement-induced damage. The premise is that “the fate [of a transplanted organ] could be sealed based on the amount of reperfusion injury,” Sacks says. So before implanting the organ, the researchers wash it with an engineered artificial protein called mirococept, which sticks to cells in the organ and blocks all three branches of the complement system. The team has already completed a safety study of the compound in people, as well as a second study in 12 kidney transplant patients that produced encouraging preliminary data that the wash protected the donor organs from ischemia-reperfusion injury. Sacks says that a larger trial of mirococept will begin later this year at about 14 kidney transplant centers in the United Kingdom.

    Hard on the eyes

    Whether mirococept will prove itself in these trials remains to be seen, but some people with rare diseases are already benefiting from recent complement discoveries. The U.S. Food and Drug Administration has approved two anticomplement treatments. One is the antibody eculizumab, which latches onto the complement protein C5 and blocks the subsequent cascade. Doctors can now prescribe it for atypical hemolytic uremic syndrome, in which complement attacks the kidneys, and paroxysmal nocturnal hemoglobinuria, in which complement destroys blood cells. The second drug, Cinryze, blocks an enzyme in the complement cascade and ameliorates hereditary angioedema, in which out-of-control complement activity can cause symptoms such as swelling of the limbs and difficulty breathing.

    Researchers predict that targeting complement will translate into other treatments. One disease that has already drawn a large amount of interest from scientists and drug companies is AMD. A combination of biochemical sleuthing and genome crunching connected complement to this macular degeneration, which usually strikes the eyes of people after age 50. In the disease, the portion of the retina that provides sharp vision deteriorates, often obliterating the central part of the visual field and leaving people unable to drive or read.

    In the late 1990s, Gregory Hageman, now at the University of Utah School of Medicine in Salt Lake City; retinal cell biologist Don Anderson of the University of California, Santa Barbara; and colleagues decided to determine what was in the small globs of material called drusen that blemish the retinas of AMD patients. Thanks to Hageman, who was then at the University of Iowa in Iowa City, the researchers had access to plenty of eyes that had been donated to the university to provide corneal transplants; once the corneas were removed, the eyes were usually thrown away.

    At first, the results of the analysis were puzzling, Anderson recalls. The initial protein the scientists identified in drusen was vitronectin, which, among other roles, naturally inhibits the activity of complement's membrane attack complex. Anderson says the team kept the findings under wraps for 2 years: “We were sitting around scratching our heads.” But further probing of drusen revealed other complement proteins.

    The case for complement's involvement in AMD grew stronger when researchers began checking for gene variants that were more common in patients with the eye disease. In 2005, four groups, including Hageman and Anderson's, reported that variants in the gene for factor H, a key complement inhibitor, boosted the risk of developing AMD. Researchers have since discovered that alterations in just three complement-related genes, including the one for factor H, account for about 75% of AMD cases in the developed world.

    Before this work began, scientists ascribed AMD's retinal damage to factors such as smoking and high levels of blood lipids and “had no suspicions it was an immune disease,” notes ophthalmologist and eye researcher Robyn Guymer of the University of Melbourne in Australia, who wasn't involved in the studies. “It really changed everyone's thinking about where to look in AMD.” In a review published earlier this year, Guymer tallied the results of that change in perspective: At least eight complement inhibitors, including eculizumab, are undergoing preclinical or clinical testing for AMD.

    On the mend.

    The complement protein C3 (green) marks cells in a regenerating mouse liver.

    CREDIT: MACIEJ MARKIEWSKI AND JOHN D. LAMBRIS

    A drug problem?

    Having two approved drugs for complement-related conditions is encouraging, researchers say. But both drugs have drawbacks, particularly their cost. A year's worth of eculizumab runs more than $400,000, and Cinryze isn't much cheaper.

    One possible route to more economical alternatives, Lambris says, involves small peptides that would be easier to manufacture. He and his colleagues have synthesized a molecule called compstatin that suppresses C3, the hub of the complement cascade. “We feel this is a good way to prevent complement activation,” says Lambris, whose university licensed the compound to a biotech company for further development. One benefit of interdicting the cascade at C3, he notes, is that it prevents complement from continually churning out compounds that switch on inflammation-promoting neutrophils. Lambris adds that several lines of evidence, including studies of other C3 inhibitors, suggest that this strategy is safe. Phase II trials, run by a second pharmaceutical company, are evaluating a modified version of the compound for AMD.

    Changing places.

    Removing an organ for transplantation unleashes complement-mediated damage.

    CREDIT: MICHELLE DEL GUERCIO/GETTY IMAGES/PHOTO RESEARCHERS RM

    With more than 30 proteins, the complement system seems to offer plenty of targets for drug designers. But compstatin highlights one of the tricky questions in complement drug design: how to tamper with the cascade without subverting its antibacterial abilities. For example, some researchers worry that blocking C3 will prevent production of the key defender C3b, which spurs macrophages and other phagocytic cells to devour invaders. “If you inhibit complement early, … you will seriously compromise innate immune function,” says immunopathologist Peter Ward of the University of Michigan Medical School in Ann Arbor.

    To limit possible side effects, some researchers favor concentrating on proteins further down the complement cascade. Eculizumab, for instance, targets the C5 protein. But Ward says he's concerned that even blocking C5 would leave people vulnerable to microbes; he notes that patients are required to get vaccinations against meningitis bacteria before receiving the antibody. Activated C5 splits into C5a, which ignites inflammation, and C5b, which joins the membrane attack complex that slays bacteria. A better alternative, Ward says, is inhibiting C5a. His lab has been investigating whether a C5a-disabling antibody is beneficial for sepsis in animals (see sidebar).

    Immunologist Michael Holers of the University of Colorado, Denver, and colleagues have taken a different approach to minimize the collateral damage of interfering with complement. They devised a combo molecule that includes part of a complement receptor—a protein that enables our cells to respond to complement proteins—and part of the complement inhibitor factor H. The idea is that the drug, dubbed TT30, will home in on tissues where complement is active. The receptor portion of TT30 sticks to any of our cells that are under complement attack and allows the inhibitor to shield them from the onslaught, but the compound isn't a general immunosuppressant because it doesn't inhibit complement throughout the body. Now being developed by a pharmaceutical company, the drug has made it through Phase I safety trials, Holers says.

    We might even find ideas for new complement therapies within our worst enemies, Lambris says. Human pathogens have fought an evolutionary battle against the complement system for hundreds of millions of years, and they've come up with some devious tricks to evade it. For example, Staphylococcus bacteria produce at least eight complement inhibitors that could serve as templates for new drugs, he says. Knowing our enemies better might help protect us from the friendly fire of one of our strongest defenses.

  5. Immunology

    Stalling Sepsis?

    1. Mitch Leslie

    Several companies have begun testing inhibitors of complement protein C5a for diseases such as atherosclerosis, and targeting the same molecule could be therapeutic for sepsis patients.

    Unlike osteoarthrisis and age-related macular degeneration, sepsis is an illness in which you'd expect complement to be involved. Typically triggered by a bacterial infection that sends the immune system into overdrive, sepsis involves runaway, body-wide inflammation, with complement at the heart of the process. “We've found that C5a [a complement protein] plays a major role in sepsis,” says immunopathologist Peter Ward of the University of Michigan Medical School in Ann Arbor.

    More than 10 years ago, Ward and colleagues showed that dosing rodents with an antibody that sticks to C5a spares them from sepsis. In subsequent experiments in which they blocked the C5a receptors in mice and studied animals that lacked these molecules, Ward's team discovered how C5a makes trouble. In 2008 the researchers reported that C5a triggers a surge in the immune system signals known as cytokines, unleashing the so-called cytokine storm that can spur numerous organs in the body to stop working.

    Several companies have begun testing C5a inhibitors for diseases such as atherosclerosis, and targeting the same molecule could be therapeutic for sepsis patients. Researchers are desperate for good news about the condition. More than 40 clinical trials of sepsis treatments have already failed, Ward notes, and the only drug approved in the United States specifically for sepsis, activated protein C, has been withdrawn from the market because of new evidence it doesn't work. Doctors can only offer general measures—such as broad-spectrum antibiotics and artificial respiration—that don't provide much benefit. In the United States, sepsis is fatal for almost 30% of the 750,000 people who fall victim to it each year. “It's a very frustrating situation right now,” Ward says.

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