News this Week

Science  14 Feb 2014:
Vol. 343, Issue 6172, pp. 714
  1. Around the World

    1 - Seoul
    New Bird Flu Strain Threatens Korean Research
    2 - Portland, Oregon
    First Fish Ready to Swim Off Endangered Species List
    3 - Mexico City
    Salamander Sightings Prove Reports of Extinction Premature
    4 - Geneva, Switzerland
    CERN to Study Possibility of 100-Kilometer Atom-Smasher

    Seoul

    New Bird Flu Strain Threatens Korean Research

    Outbreak.

    Korean health officials remove eggs from a duck farm suspected of carrying bird flu.

    CREDIT: YONHAP/AFP/GETTY IMAGES/NEWSCOM

    A dangerous new strain of bird flu in South Korea has spread nationwide despite efforts to clamp down on the virus. Authorities have culled 2.8 million domestic chickens and ducks since the outbreak began, and the strain has also killed dozens of Baikal teal and other migratory birds. As yet, there are no reports of human infections. Scientists are puzzling over where the H5N8 strain, never before seen in a highly pathogenic form, originated.

    Researchers are now scrambling to keep the virus out of the country's premier poultry research center. A wild goose infected with the virus was found dead on 1 February just 10 kilometers from the Suwon campus of the National Institute of Animal Science (NIAS), near Seoul. The facility houses more than 13,000 hens and nearly 5000 ducks for research on breed improvement and animal husbandry. "If the virus infects the facility, we would cull all of the poultry," says NIAS's Yong-sup Song. That would put a serious dent in the center's genetic resources and set back ongoing research programs. http://scim.ag/avianflu

    Portland, Oregon

    First Fish Ready to Swim Off Endangered Species List

    CREDIT: RICK SWART/ODFW

    A tiny minnow has bounced back from near-extinction. The U.S. Fish and Wildlife Service (FWS) says populations of the Oregon chub (Oregonichthys crameri) are healthy enough to remove the 9-cm-long fish from its list of threatened and endangered wildlife. Last week's announcement marks the first time an endangered fish has recovered enough to be delisted.

    The chub lives in beaver ponds, oxbows, and calm streams of the Willamette River Valley of western Oregon. After the 1940s, populations plummeted from habitat damage by logging, pollution, and dams. When the fish was listed by FWS in 1993, only nine known populations remained. Predation by largemouth bass and other non-native fishes was the largest threat to the remaining chub.

    Since then, the Oregon Department of Fish and Wildlife and other groups started 20 new populations of the chub in predator-free ponds. And dozens of other surviving populations have been discovered in the wild. Changes to dam management have lowered the threat to remaining habitat. FWS will accept expert and public comment on its proposal to delist until 7 April.

    Mexico City

    Salamander Sightings Prove Reports of Extinction Premature

    CREDIT: © MAXIMILIAN WEINZIERL/ALAMY

    The axolotl salamander's only known home in the wild, the Xochimilco canals of Mexico City, has become increasingly polluted, but recent reports of the amphibian's extinction have been (not-so-greatly) exaggerated.

    Two weeks after announcing that months of searching the canals hadn't turned up any axolotls, scientists in Mexico City have some good news: two of the unique salamanders were spotted on 4 February. "There's been an alarming reduction in population density," says Luis Zambrano, a biologist at the National Autonomous University of Mexico in Mexico City who studies the axolotl. "But I can guarantee that [the axolotl] is not yet extinct" in the wild.

    Axolotls (Ambystoma mexicanum) have long intrigued scientists with their odd appearance, their impressive ability to regenerate limbs, and the fact that they don't undergo metamorphosis like other salamanders, instead retaining their feathery gills and other tadpolelike features into adulthood. Axolotls are popular pets and lab animals, but Zambrano says no reintroduction efforts with captive populations will be tried until scientists are positive the axolotl is "100% extinct" in the wild.

    Geneva, Switzerland

    CERN to Study Possibility of 100-Kilometer Atom-Smasher

    Scientists at the European particle physics laboratory will study plans for a pair of circular particle colliders 80 to 100 kilometers in circumference, to be built one after the other in the same tunnel. The plan would depart from the current vision for global particle physics, in which the successor to CERN's current 27-kilometer-long Large Hadron Collider (LHC) would be a straight linear collider that would smash electrons into positrons. The LHC smashes protons and in 2012 discovered the Higgs boson.

    In the new scheme, physicists would build a somewhat lower energy circular electron-positron collider and later a proton collider able to reach energies seven times as high as the LHC. In reusing the tunnel, CERN would repeat a strategy that reduced costs during the construction of the LHC. The 5-year study is "not about digging holes in the ground now or asking governments for money," says CERN spokesman James Gillies. "It's just about considering the technology that would be available in 20 or 30 years." http://scim.ag/atomsmasher

  2. Newsmakers

    Three Q's

    Thevis

    CREDIT: IMAGO/CAMERA 4/NEWSCOM

    Each Olympics, there is a race between athletes seeking an artificial advantage and the antidoping experts trying to catch them. At the Winter Olympics in Sochi, a new chemical may be in the mix. Mario Thevis, a forensic chemist at the German Sport University Cologne, tested a substance obtained by German journalists during an undercover investigation of a Russian scientist selling "full size MGF" for $1000 per milligram. Thevis confirmed the sample contained mechano growth factor (MGF), which can prompt muscle growth and is undetectable by current testing methods.

    Q:What is the substance you found in the sample?

    M.T.:The closest way to describe it is human IGF-1 isoform 4. The mRNA of isoform 4 is elevated when mechanical stress is applied to muscle tissue. We could deduce that we were dealing with a highly pure and therefore probably highly dangerous substance.

    Q:What might the side effects be?

    M.T.:We don't know. It could cause any of the side effects associated with IGF-1, such as cardiovascular issues. Some of the growth factors also have cancer-causing effects. We can't prove or rule out any of these.

    Q:Now that you know this might be in circulation among athletes, why can't you test for it right away?

    M.T.:Practically we can, but we have to demonstrate that our test is fit for the purpose. We have to evaluate whether our detection limits are in the range for physiological or therapeutic amounts, even though we have no idea how much that would be.

    Extended interview at http://scim.ag/_sochi.

  3. Random Sample

    ScienceLIVE

    Join us on Thursday, 20 February, for a live chat with experts on assessing the harm of drugs for rational drug policy. http://scim.ag/science-live

    Charles Darwin Gets Busted

    CREDIT: © UCL, INSTITUTE OF MAKING/ROBERT EAGLE (3)

    An empty pedestal has become the inspiration for a collection of zany sculptures of Charles Darwin. Students and staff from University College London competed to fill a void left by the relocation of an original bust of the eminent naturalist.

    The competition's seven entries—on display in a 7-week-long exhibition titled Darwin (or) Bust at the Grant Museum of Zoology in London—are based on 3D scans of the original plaster bust, which was moved to a newly constructed building on campus. The new designs come with a twist. One entry renders Darwin's face as a collage of pages from his seminal book, The Origin of Species; another, a likeness molded from a transparent gel through which ants will be enticed to tunnel; and a third has a pensive-looking Darwin crocheted out of yarn. The winning entry was announced at the exhibit's grand opening on 12 February, the 205th anniversary of Darwin's birth. We wanted people to "get creative, get technical, [and] get messy" while reimagining the great man, says Grant Museum curator Mark Carnall.

  4. The Coming Copper Peak

    1. Richard A. Kerr

    Production of the vital metal will top out and decline within decades, according to a new model that may hold lessons for other resources.

    Headed down.

    Miners must move megatons of low-grade copper ore at the Zijinshan mine in South China.

    CREDIT: YANG ZHIPING/COLOR CHINA PHOTO/AP IMAGES

    If electrons are the lifeblood of a modern economy, copper makes up its blood vessels. In cables, wires, and contacts, copper is at the core of the electrical distribution system, from power stations to the delicate electronics that can display this page of Science. A small car has 20 kilograms of copper in everything from its starter motor to the radiator; hybrid cars have twice that. But even in the face of exponentially rising consumption—reaching 17 million metric tons in 2012—miners have for 10,000 years met the world's demand for copper.

    But perhaps not for much longer. A group of resource specialists has taken the first shot at projecting how much more copper miners will wring from the planet. In their model runs, described this month in the journal Resources, Conservation and Recycling, production peaks by about midcentury even if copper is more abundant than most geologists believe. That would drive prices sky-high, trigger increased recycling, and force inferior substitutes for copper on the marketplace.

    Predicting when production of any natural resource will peak is fraught with uncertainty. Witness the running debate over when world oil production will peak (Science, 3 February 2012, p. 522). And the early reception of the copper forecast is mixed. The work gives "a pretty good idea that likely we'll get a peak somewhere around midcentury," says industrial ecologist Thomas Graedel of Yale University. Technological optimists disagree. "Not that it couldn't happen, but I don't think it's likely to happen," says resource economist John Tilton, research professor emeritus at the Colorado School of Mines in Golden. New and better technology for extracting copper from the earth has always come to the rescue before, he notes, so he expects a much-delayed peak that businesses and consumers will comfortably accommodate by recycling more copper and using copper substitutes.

    The copper debate could foreshadow others. The team is applying its depletion model to other mineral resources, from oil to lithium, that also face exponentially escalating demands on a depleting resource.

    So far, so good

    The techno-optimists were right about copper in the past. From nearly nothing in the mid-18th century, copper production soared along an exponential curve notched only by world wars and economic crises. That's all the more impressive considering the accompanying decline in the richness, or grade, of the ore being mined. Anyone extracting a mineral resource goes for the richest, most easily mined deposits first, so ore grades ran from 10% to 20% copper until late in the 19th century and then plummeted to 2% to 3% in the early 20th century. Since the mid-1990s, the world copper grade has been just below 1% and in slow decline, according to data compiled by resource geologist Gavin Mudd of Monash University, Clayton, in Australia, in a 2013 paper in the International Journal of Sustainable Development.

    Even though the available ores have become poorer, forcing miners to claw ever greater volumes of rock from kilometer-deep open pit mines, the price of copper has trended downward since 1900 (with a notable spike since 2005 driven by China's hunger for raw materials). Multiple factors have driven the price decline. Geologists found a new type of copper deposit—the porphyry ores of buried magma formations—that is now the source of most of the world's copper. And lately they have been finding extractable porphyry copper faster than it is produced, according to Richard Schodde of MinEx Consulting in Melbourne, Australia. Equipment manufacturers have built humongous shovels and dump trucks to move huge volumes of porphyry ore. And chemical engineers have developed processes such as heap leaching—trickling weak sulfuric acid through piled crushed ore—to get copper out of low-grade ore.

    Even with the technology that is now in hand—not what might be developed someday—the copper now within reach of miners is considerable. At this past October's Geological Society of America meeting, U.S. Geological Survey researchers led by geologist Jane Hammarstrom of USGS headquarters in Reston, Virginia, reported their new assessment of the porphyry copper yet to be discovered that could be economically mined with current technology. By inferring how much copper might be beneath geologically likely terrains around the world, the group estimated that 2.2 billion metric tons of economically extractable metal remain to be found. At current rates of production, that's a 125-year supply for the world.

    Not so fast

    The world's copper future is not as rosy as a minimum "125-year supply" might suggest, however. For one thing, any future world will have more people in it, perhaps a third more by 2050. And the hope, at least, is that a larger proportion of those people will enjoy a higher standard of living, which today means a higher consumption of copper per person. Sooner or later, world copper production will increase until demand cannot be met from much-depleted deposits. At that point, production will peak and eventually go into decline—a pattern seen in the early 1970s with U.S. oil production.

    Heading up, until …

    The world has been producing ever larger amounts of copper (left, in a purifying electrolytic bath), but given the planet's finite endowment, production must peak. A model projection has production peaking by 2040.

    CREDITS (TOP TO BOTTOM): ADAPTED FROM S. NORTHEY ET AL., RESOURCES, CONSERVATION AND RECYCLING 83 (FEBRUARY 2014) © PUBLISHED BY ELSEVIER B.V.; AXEL SEIDEMANN/AP PHOTO

    For any resource, the timing of the peak depends on a dynamic interplay of geology, economics, and technology. But resource modeler Steve Mohr of the University of Technology, Sydney (UTS), in Australia, waded in anyway. For his 2010 dissertation, he developed a mathematical model for projecting production of mineral resources, taking account of expected demand and the amount thought to be still in the ground. In concept, it is much like the Hubbert curves drawn for peak oil production, but Mohr's model is the first to be applied to other mineral resources without the assumption that supplies are unlimited.

    Now Mohr and Mudd have teamed up with resource specialists Stephen Northey of Australia's national research agency CSIRO in Clayton, Zhehan Weng of Monash Clayton, and Damien Giurco of UTS to apply Mohr's model to copper. For their study, the group drew on a database of the extractable copper at all known mine sites that was compiled by Mudd and Weng and published in 2012. The group assumed that per capita demand for mined copper would continue to rise at the historical rate of 1.6% per year and that the world's population would grow from today's 7.1 billion people to 10 billion in 2100. They taught the model how to behave realistically by fitting it to past copper production for each country and type of deposit. In the model, increasing demand elicits increased production at existing mines and the opening of new mines.

    The model delivers some good news, suggesting that production can rise to meet expected demand for the next 2 to 3 decades. "It's not a story of doom and gloom, of running out tomorrow," Giurco says, "but rather of needing to be more mindful of use." But trouble comes in the longer term. With the amount of extractable copper in the Mudd and Weng compilation, the model shows production peaking just before 2040; after that, copper can't be extracted from depleted mines any faster, no matter how high the price.

    Increasing the amount of accessible copper in the model by 50% to account for what might yet be discovered moves the production peak back only a few years, to about 2045. It just takes a lot of copper to satisfy exponentially growing demand, Mohr says. In additional model runs performed at the request of Science, Mohr found that even doubling the available extractable copper pushes peak production back only to about 2050. And quadrupling it—an optimistic projection indeed—would mean the world would run short of copper by about 2075.

    Copper trouble spots

    So far, so bad—but technological optimists are quick to note that human ingenuity has confounded the gloom-sayers before. "As a society, we have tended to underestimate how much copper is out there, and how creative society can be about extracting it," Tilton says. He points out that in the 1970s, USGS estimated that about 1.6 billion tons of copper could be extracted with current technology. Today, the equivalent USGS figure is 3.1 billion tons. "And it's very likely to double again," Tilton says, even without including the copper on the ocean floor along midocean ridges. "We know the copper's there—it's a matter of resolving technical problems allowing extraction," he says.

    Postpeak options.

    The price spike at peak copper will drive even more recycling of scrap (above). U.S. pennies used to be pure copper (far left), but now they are copper-plated zinc; substitutions in major uses of copper will be far less satisfactory.

    CREDITS (TOP TO BOTTOM): BRUCE KELLMAN/THE NEWS TRIBUNE/AP PHOTO; MARTY LEDERHANDLER/AP PHOTO

    Graedel doesn't go that far, saying the world has been so thoroughly explored for copper that most of the big deposits have probably already been found. Although there will be plenty of discoveries, they will likely be on the small side, he says. As for technological breakthroughs on a par with those in the past, he says, "you can't tell."

    Furthermore, the models don't take into account constraints on copper mining that could make things worse. "The critical issues already constraining the copper industry are social, environmental, and economic issues," Mudd writes in an e-mail. Any process intended to extract a kilogram of metal locked in a ton of rock buried hundreds of meters down inevitably raises issues of energy and water consumption, pollution, and local community concerns. And such "environmental and societal constraints are getting stronger," Mudd says.

    Mudd has a long list of copper mining trouble spots. The Reko Diq deposit in northwestern Pakistan close to both Iran and Afghanistan holds $232 billion of copper, but it is tantalizingly out of reach, with security problems and conflicts between local government and mining companies continuing to prevent development. The big Panguna mine in Bougainville, Papua New Guinea, has been closed for 25 years, ever since its social and environmental effects sparked a 10-year civil war that left about 20,000 dead.

    And, looking ahead, on 15 January the U.S. Environmental Protection Agency issued a study of the potential effects of the yet-to-be-proposed Pebble Mine on Bristol Bay in southwestern Alaska. Environmental groups had already targeted the project, and the study gives them plenty of new ammunition, finding that it would destroy as much as 150 kilometers of salmon-supporting streams and wipe out more than 2000 hectares of wetlands, ponds, and lakes.

    As a crude way of taking account of such social and environmental constraints on production, Northey and colleagues reduced the amount of copper available for extraction in their model by 50%. Then the peak that came in the late 2030s falls to the early 2020s, just a decade away.

    After the peak

    Whenever it comes, the copper peak will bring change. Alternative materials can replace copper in many uses, but substitution in some is easier than in others. In 1982, the U.S. copper penny—at least 88% copper since 1793—became 97.5% zinc and just 2.5% copper, mostly as copper plating, to discourage people from melting down the coins for their copper. But Graedel and his Yale colleagues reported in a paper published on 2 December 2013 in the Proceedings of the National Academy of Sciences that copper is one of four metals—chromium, manganese, and lead being the others—for which "no good substitutes are presently available for their major uses."

    Recycling is more promising. Copper is already the third most recycled metal after iron and aluminum. Roughly 50% of the copper that goes out of service is returned to use, Graedel says. Governments could increase that figure by requiring product designs that, say, made recovery of copper wiring from cars easier and less expensive. Scarcity-driven price hikes will also boost recycling, Graedel notes.

    Copper is far from the only mineral resource in a race between depletion—which pushes up costs—and new technology, which can increase supply and push costs down. Gold production has been flat for the past decade despite a soaring price (Science, 2 March 2012, p. 1038). Much crystal ball–gazing has considered the fate of world oil production. "Peakists" think the world may be at or near the peak now, pointing to the long run of $100-a-barrel oil as evidence that the squeeze is already on. Mohr's model is only slightly less pessimistic: It forecasts an oil peak in 2019, he reported in his dissertation.

    Coal will begin to falter soon after, his model suggests, with production most likely peaking in 2034. The production of all fossil fuels, the bottom line of his dissertation, will peak by 2030, according to Mohr's best estimate. In the studies Mohr has had a hand in publishing, only lithium, the essential element of electric and hybrid vehicle batteries, looks to offer a sufficient supply through this century. So keep an eye on oil and gold the next few years; copper may peak close behind.

  5. Strength in Numbers?

    1. Mitch Leslie

    Some mammalian cells are loaded with extra sets of chromosomes, a state called polyploidy. What on Earth for?

    A little extra.

    A human cell with twice the normal number of chromosomes (white) attempts to divide.

    CREDIT: NEIL J. GANEM/BOSTON UNIVERSITY

    A dividing cell generally follows a simple rule. After duplicating its DNA, the cell splits, yielding two daughter cells. That's why the movies of dividing mouse liver cells shot several years ago by Andrew Duncan, then a postdoc in Markus Grompe's group at the Oregon Health & Science University in Portland, flabbergasted his lab mates. "We saw a single cell giving rise to three and four daughter cells," says Duncan, who is now a tissue biologist at the University of Pittsburgh in Pennsylvania. And though chromosomes normally line up neatly across the middle of a cell before it divides, the chromosomes in many of the liver cells were arranged in unconventional formations, including multiple clusters.

    The parental liver cells were forced to go through unusual maneuvers because they were polyploid, carrying extra sets of chromosomes. Polyploidy is rife among plants, insects, fish, and some other groups of organisms. But most human cells are diploid, outfitted with two sets of chromosomes that trace back to the set each provided by an egg and a sperm. Indeed, extra chromosomes usually spell trouble in mammalian cells. A few normal cells in people and other mammals, however, brim with extra genome copies—sometimes as many as a thousand. The contortions of the liver cells were surprising, but they had long been known to have a surfeit of chromosomes—as do cells in the heart and bone marrow.

    For decades, researchers have speculated about whether polyploidy offers any advantages to mammalian cells, such as ramping up protein synthesis, but haven't been able to test their ideas. That has changed with the identification of several proteins that help regulate polyploidy. By cranking cells' allotment of chromosomes up or down, scientists recently have begun to explore the possible function of the odd cellular state. Do the extra chromosomes simply add bulk to cells that need it? Do they give cells reserve capacity that enables them to respond to stress and damage? "The real unanswered question is why any cell type is polyploid," says developmental geneticist Robert Duronio of the University of North Carolina (UNC), Chapel Hill. "We are poised to begin answering that question."

    And even though the mystery of polyploidy's benefits remains unsolved, some researchers already hope to exploit the phenomenon. They are trying to turn polyploidy against certain cancers, compelling cells to cease their out-of-control division.

    Risky excess

    Polyploidy can seem like "a dangerous escapade," as Duronio and his colleagues put it in a 2009 paper. For cells that usually get along just fine with two sets of chromosomes, even one additional chromosome can be disastrous. An extra copy of chromosome 21 during development produces the disabilities of Down syndrome, for instance.

    There's another potential drawback to polyploidy. "It can drive cancer," says David Pellman, a cell biologist and pediatric oncologist at the Dana-Farber Cancer Institute in Boston. He points to a 2013 Nature Genetics paper by Rameen Beroukhim, also of Dana-Farber, and colleagues that reported duplicated genomes in 37% of cancers. Polyploidy doesn't lead to cancer in every case, Pellman says, but it's a big enough risk that many cells go to great lengths to thwart it. p53, the watchful protein dubbed the guardian of the genome, often prompts cells with abnormal amounts of DNA to commit suicide or to curtail division. To become polyploid, therefore, cells have to disable it and other safeguards that protect against genome damage, notes biologist Gustavo Leone of Ohio State University, Columbus.

    Researchers have gradually acquired a good grasp of the molecules and mechanisms that make cells polyploid, thanks mainly to their work on the cell cycle. A cell's life cycle includes milestones such as DNA duplication and division. An intricate network of proteins controls the cell's progress through the cycle, pushing it forward or holding it back. Under the right circumstances, researchers have found, some of these proteins steer cells toward polyploidy.

    To tweak the chromosome content of cells, several research teams have recently genetically engineered mice to make more or less of these polyploidy promoters. For example, biochemist Katya Ravid of Boston University School of Medicine and colleagues enhanced polyploidy to test its role in megakaryocytes, hefty immune cells that dwell in the bone marrow and generate the platelets that help stanch bleeding. Megakaryocytes often harbor more than 100 copies of their genome, and researchers conjectured that the extra genes help the cells crank out platelets.

    In 2010, Ravid's team engineered mice to manufacture excess amounts of a polyploidy-promoting protein. Although the alteration boosted the number of chromosome sets the cells contained, it didn't cause a corresponding rise in platelet numbers, the team revealed in The Journal of Biological Chemistry. Ravid suggests that polyploidy instead benefits megakaryocytes by boosting production of proteins that the cells need for structural support and sticking to their neighbors.

    Bonus DNA.

    The polyploid cells in mammalian bodies differ in their location, function, and number of chromosome sets (table). In a liver cell (right), the multiple chromosome copies (blue) have sorted into three clusters in preparation for cell division.

    CREDIT: (RIGHT) ANDREW W. DUNCAN AND MARKUS GROMPE

    Bulking up

    Biophysical engineer Dennis Discher of the University of Pennsylvania School of Medicine offers another explanation. He suspects that polyploidy helps a megakaryocyte in the same way a high-calorie diet helps a sumo wrestler—by increasing bulk. A membrane perforated by small pores separates the bone marrow from the bloodstream, and a megakaryocyte has to stay on the bone marrow side. Discher and his colleagues recently examined what size pores different types of bone marrow cells could slip through, and they found that megakaryocytes had trouble squeezing through even the largest openings, probably because of their chromosomepacked nuclei. "If you ask me why this cell is polyploid, I'd say it helps anchor the body of the cell in the marrow," says Discher, whose team reported its findings in the 19 November 2013 issue of the Proceedings of the National Academy of Sciences.

    Researchers already have evidence from other species that extra heft is a benefit of polyploidy. In a 2012 study of fruit flies, Terry Orr-Weaver of the Massachusetts Institute of Technology and her colleague Yingdee Unhavaithaya found that when they reduced the levels of a polyploidy-stimulating protein in cells forming the blood-brain barrier in flies, the cells shrank and the barrier became leaky. The pair also showed that enlarging the undersized cells restored a tight seal. Boosting the size of existing cells might cause less disruption than producing more cells through division, which requires that a cell disengage from its neighbors, notes cell biologist Brian Calvi of Indiana University, Bloomington.

    Yet for one mammalian cell type that takes polyploidy to the extreme, work by Leone's team downplays the size connection. Cells in the outer layer of embryos, known as trophoblast giant cells, are polyploidy champions—in mice they pack up to 1000 genome copies. The cells help the embryo implant in its mother's womb, and researchers have suggested that adding chromosomes allows the cells to quickly enlarge, enabling the embryo to infiltrate the uterine lining.

    Leone and his colleagues deleted genes for polyploidy-promoting proteins from trophoblast giant cells in mice, anticipating that embryos would die because implantation would suffer. "We were expecting that polyploidy is really significant," Leone says. Although the giant trophoblast cells were smaller than normal and carried fewer chromosomes, the mouse embryos lived and grew up into seemingly healthy adults, the researchers reported in Nature Cell Biology in 2012.

    Deep reserves

    For the heart and the liver, two hard-working organs that also teem with polyploid cells, researchers are exploring a different explanation for polyploidy: The extra chromosomes boost performance under trying conditions and increase overall resilience. Indeed, "polyploidy may be an important stress response or adaptation" for many cell types, says cell biologist Donald Fox of Duke University Medical Center in Durham, North Carolina.

    Support for that notion comes from a study of the mouse heart, in which almost all the cells sport four sets of chromosomes. In 2010, stem cell biologist Thomas Braun of the Max Planck Institute for Heart and Lung Research in Bad Nauheim, Germany, and colleagues examined genetically altered mice whose muscle cells—including those in the heart—were missing a gene that spurs polyploidy. Although the gene's absence didn't make all the animals' heart cells diploid, it did reduce the number of chromosome sets they contained by about one-third.

    "At baseline conditions, they are pretty normal," Braun says of the mice. However, deficiencies appeared when the rodents had to cope with setbacks such as a heart attack. The hearts of animals with reduced polyploidy pumped less blood after an induced heart attack than did the hearts of control animals, the group reported in Circulation Research. How polyploidy enables the heart to rebound remains unclear, Braun says.

    The work by Duncan and his colleagues on liver cells also backs the stress-response hypothesis. Unlike most mammalian organs, the liver has a remarkable ability to regenerate after injury. The liver is also well stocked with polyploid cells: In humans, about 50% of the liver cells called hepatocytes carry extra sets of chromosomes.

    Duncan's team had originally explored whether the polyploid cells within the liver are "terminally differentiated," meaning that they had become mature cells that don't divide and help replenish the organ. So the team transplanted polyploid hepatocyte cells into mice whose livers had been partially removed. "To our great surprise, they regenerated the liver perfectly," Duncan says.

    That's when Duncan put the liver cells under the microscope, turned on the camera, and noticed their unorthodox division style. The researchers discovered something else unusual about the cells. As the team revealed in Nature in 2010, when many of the polyploid cells divided, they spawned diploid daughter cells. But often these diploid daughters hadn't quite returned to normal—many of them had gained or lost an individual chromosome, a condition called aneuploidy that is generally considered ominous. "Most cancer folks will tell you that aneuploidy is synonymous with cancer," Duncan says.

    But some researchers have proposed that aneuploidy can create useful genetic diversity in a tissue or organ, allowing cells to add a copy of a beneficial gene or throw out a copy of a detrimental one. And when Duncan and colleagues studied an example of liver regeneration in mice, they found that sites where regrowth occurred were rich in aneuploid cells. They have discovered that aneuploid cells are abundant in human livers, too.

    Duncan now hypothesizes that polyploidy in the liver is a roundabout way to produce aneuploid cells that have regenerative properties. His team is now working to confirm that these cells spur regeneration in people suffering from hepatitis B, in which a virus devastates the liver. Some patients die unless they get a liver transplant, but others survive as sections of the organ regenerate. The researchers are collecting tissue samples to determine if areas of the liver that regrow are high in aneuploid cells.

    But the idea that polyploidy helps tissues regenerate remains a hypothesis, as findings from Leone's group and that of Alain de Bruin, a pathologist and veterinarian at Utrecht University in the Netherlands, emphasize. They genetically engineered mice so the animals' livers lack two polyploidy-promoting proteins. "We can generate a mouse whose liver is almost entirely [diploid] cells," De Bruin says. Both teams expected that the animals would suffer ill effects. Instead, the mice were vigorous, each group reported in Nature Cell Biology in 2012, and their livers were no less able to regrow after injury. The mice De Bruin and colleagues studied, for example, could restore their livers after surgical removal of two-thirds of the organ. "This polyploidization does not have an effect on regeneration or on proliferation rate," De Bruin says.

    Double down.

    The chromosome copies from a polyploid liver cell arranged by size, showing that the cell carries four copies of almost every one.

    CREDIT: A. DUNCAN ET AL., GASTROENTEROLOGY 6 (JANUARY 2012) © 2012 AGA INSTITUTE, PUBLISHED BY ELSEVIER INC.

    The work from both teams also undermines another older polyploidy hypothesis. The liver, De Bruin notes, "is all the time exposed to toxins." Hepatocytes work hard to detoxify all those noxious substances, and some researchers had speculated that their extra genetic material could boost the output of proteins crucial to this. Yet the mice whose livers had reduced polyploidy had no problems breaking down toxins, De Bruin's group found.

    Exploiting polyploidy

    Even as they wrestle with mystery of polyploidy, researchers wonder whether they can put what they've learned to use. Leukemia biologist John Crispino of Northwestern University's Feinberg School of Medicine in Chicago, Illinois, and his colleagues have trained their sights on a type of acute myeloid leukemia, triggered by megakaryocytes, that kills most adults who develop it. Mature megakaryocytes don't divide, but in this form of cancer, the cells remain immature, don't become polyploid, and replicate prodigiously, causing the leukemia. Crispino and colleagues propose that forcing the cells to become polyploid and mature might treat the cancer.

    The team revealed in Cell in 2012 that it had identified more than 200 compounds that, in lab dishes, spur polyploidy in human megakaryocytes. One of these molecules, alisertib, is already under-going clinical trials for several other types of cancer—though not because of its ability to stimulate polyploidy. Crispino's group is now trying to organize an initial safety trial of the drug in people with acute myeloid leukemia.

    Although polyploidy research has recorded some progress in recent years, the field still hasn't nailed down the benefits polyploidy provides to different mammal cell types. To move forward, Leone says, researchers should take a cue from plant biologists, who have tested polyploidy's advantages in specific environmental conditions, showing that it boosts tolerance for salinity (Science, 9 August 2013, p. 658). Scientists could perform similar studies on liver cells, for example, by gauging whether polyploidy helps them deal with different diets. Delving further into polyploidy's cellular roles will probably produce some surprises, UNC Chapel Hill's Duronio predicts. "There are going to be many uses for polyploidy, and we are just scratching the surface."

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