News this Week

Science  26 Aug 2011:
Vol. 333, Issue 6046, pp. 1076
  1. Around the World

    1 - Washington, D.C.
    FDA Approves Gene-Targeted Melanoma Drug
    2 - Kugluktuk, Nunavut, Canada
    Geologists Hope to Claim Piece of Arctic for Canada
    3 - Kandakadu, Sri Lanka
    Bananas a Flashpoint for Human-Elephant Conflict
    4 - Mumbai, India
    Hints of Higgs Boson Appear Weaker
    5 - Washington, D.C.
    New U.S. Conflict of Interest Rules

    Washington, D.C.

    FDA Approves Gene-Targeted Melanoma Drug

    A new kind of melanoma drug that targets a molecular weak spot in cancer cells received approval last week from the U.S. Food and Drug Administration.

    The drug, called vemurafenib or Zelboraf, blocks a protein made by a mutated gene called BRAF that spurs tumor growth. In a clinical trial published last spring, advanced melanoma patients with the BRAF mutation who took vemurafenib lived significantly longer than patients on a standard drug. Only the 50% or so of advanced melanoma patients whose tumors carry the BRAF mutation will receive the new drug.

    Vemurafenib, which is made by Roche and Plexxikon (now owned by Daiichi Sankyo), is the latest example of several remarkably effective new gene-targeted cancer therapies. However, often these drugs eventually stop working because tumors develop resistance. Researchers hope that combining vemurafenib with a second drug will prolong patient survival.

    Kugluktuk, Nunavut, Canada

    Geologists Hope to Claim Piece of Arctic for Canada

    Break up.

    Icebreakers in the Arctic


    A geological survey team of Canadian scientists set out 18 August to map the last uncharted regions of the Arctic sea floor. This is the last leg of Canada's project to collect geological data to support their claim to the Arctic Ocean's sunken mountain range, the Lomonosov Ridge, and the potential natural resources it holds. Canada is facing a 2013 deadline to make their case to the United Nations.

    Under the U.N. Convention on the Law of the Sea, a country can claim land up to 200 nautical miles off its shore. Canada, Russia, and Denmark (through Greenland) are each trying to determine whether the ridge is an extension of their continental shelf.

    Canada has spent 10 years and $109 million on the project so far. The 6-week cruise will try to place the last piece of the puzzle, a 2000-kilometer-long extension of the Lomonosov Ridge called the Alpha Ridge that runs north of the Yukon coast, which has remained virtually unexplored.

    The Canadian research team is joined by American researchers on a second icebreaker. Russia is performing similar mapping missions and is expected to submit its claim this year. Denmark plans to make one in 2014.

    Kandakadu, Sri Lanka

    Bananas a Flashpoint for Human-Elephant Conflict

    Endangered Asian elephants may face a new threat, conservationists say: bananas. Dole Food Company and local partner Letsgrow recently established a banana plantation on about 890 hectares of scrubland near Kandakadu, at the edge of Somawathiya National Park in Sri Lanka's war-ravaged North Central Province. Conservationists claim that up to half of the plantation's land is protected forest—a claim Dole denies.

    Dole contends that the Sri Lanka Army, which partners with Letsgrow on agricultural ventures, granted them the rights to the Kandakadu land. But conservationists insist that the army does not own the land, and that part of the plantation belongs to the government's National Livestock Development Board.

    How the plantation in Somawathiya will affect elephants is unclear. Marty Ordman, a spokesperson for Dole, asserts that elephants are “not very common” in the area around Dole's plantation. But lands surrounding national parks are important to elephants in those parks, explains Shermin de Silva, director of the Uda Walawe Elephant Research Project in southern Sri Lanka. “Large animals need a large area to roam in,” she says. “They don't just stay where people say it's OK for them to be.”

    Mumbai, India

    Hints of Higgs Boson Appear Weaker

    Last month physicists working with the world's highest-energy atom-smasher—the Large Hadron Collider (LHC) at the European particle physics laboratory, CERN, near Geneva, Switzerland—reported possible evidence of the Higgs boson, the key to physicists' explanation of how all particles get their mass. At the biannual Lepton Photon conference this week, however, the same two teams reported that, with more data, those signs appear weaker. That suggests the signals could be statistical fluctuations in the “background” produced by decays of familiar particles.

    “If you add 50% more data, you expect the signal to grow, and it does not,” says Vivek Sharma of the University of California, San Diego, who reported the new results of the team working with the CMS particle detector. Still, it's not certain that the signals are just background fluctuations, says Bill Murray of Rutherford Appleton Laboratory near Didcot, U.K., who works with the ATLAS detector, also fed by the LHC. “The old data and the new data are telling different stories,” he says. “Which one is telling us the right story, we can't yet say.”

    Researchers should be able to spot the particle or rule it out by year's end, Sharma says: “If it's not there, it will be known to be science fiction by December.”

    Washington, D.C.

    New U.S. Conflict of Interest Rules

    The U.S. government this week issued new rules aimed at cracking down on financial conflicts of interest in biomedical research. The update of a 16-year-old regulation will require researchers funded by the Public Health Service to report more of their income from drug companies and other outside sources to their institutions. The regulations also require that institutions, rather than investigators, determine if any payments constitute a conflict.

  2. Reformer Takes Reins in Rome


    The Italian National Research Council (CNR)—a €1 billion basic research agency with 100 institutes around the country—may be headed for some major changes with the appointment on 13 August of Francesco Profumo, the successful, reform-minded rector of the Polytechnic University of Turin, as CNR's new president. Italian scientists say he is likely to modernize and revitalize the agency, which has been plagued by budget cuts. While at the Polytechnic University, Profumo, 58, worked hard to build international ties, turn scientific research into economic development and innovation, and forge tight collaborations with industry. Profumo says he'll try some of the same recipes at CNR and will spur Italy to get more research money from the European Union. Italy currently contributes 14% of the E.U.'s research funds but receives only 9% of the grants the union distributes.

    “Profumo has proved his exceptional skills in coordinating research, technology, and industry, and he will give CNR a central role in applied research,” says Luigi Donato, founder and former head of the CNR Institute of Clinical Physiology in Pisa. “The latter aspect is crucial in this moment of financial crisis.”

  3. Random Samples

    They Said It

    “To be clear. I believe in evolution and trust scientists on global warming. Call me crazy.”

    —Tweet by 2012 Republican presidential candidate Jon Huntsman on 18 August after Texas governor and Republican candidate Rick Perry said that evolution is “a theory that's out there” and questioned whether climate scientists manipulated data for money.

    Witnessing a Watery Junkyard


    During World War II, German U-boats sank dozens of U.S. ships off the coast of North Carolina, creating a watery junkyard known as the Graveyard of the Atlantic. Those ships are now the target of scientists from Woods Hole Oceanographic Institution (WHOI), who are using a remotely operated vehicle outfitted with underwater 3D cameras to capture images of sunken ships previously located with side-scan sonar.

    In mid-August, Evan Kovacs, director of 3D photography for WHOI's Advanced Imaging and Visualization Lab, and his team took new 3D and 2D images of the ships (shown here), as part of an ongoing project with the National Oceanic and Atmospheric Administration and the National Park Service to study their deterioration and impact on the environment. “Video and imagery have always been key for marine archaeology,” Kovacs says, “but before 3D, it's [been] difficult to pull hard, quantitative data out of it.” The 3D data, he says, allow scientists to analyze rates of collapse and corrosion. And, he adds, 3D images are a great outreach tool: “It's an insanely immersive environment.”

    A(nother) Modest Proposal


    Lions roaming the streets of Athens, gorillas swinging from traffic lights in Spain—sure, it might be dangerous, but think of the ecotourism dollars! That revenue could provide a badly needed boost to troubled nations' economies, says the (so-called) Coalition of Financially Challenged Countries With Lots of Trees (CoFCCLoT). In their “Modest Proposal,” published in Biotropica on 16 August, CoFCCLoT also suggests that wealthy Western nations reforest their land, which would help slow climate change and provide new habitat for displaced and endangered species such as bears and wolves.

    Such a proposal may sound unreasonable, but it is the kind of environmentally conscious action that the West expects of countries that harbor tropical forest, says conservation scientists Erik Meijaard and Douglas Sheil, who created the fictitious coalition. Conservationists in wealthy countries shouldn't complain about tropical deforestation, but then drink a cup of Brazilian coffee every morning and buy cheap palm oil, the authors say.

    Meijaard and Sheil hope to use satire to highlight such double standards. “What we're trying to show is the viewpoints that people are having are very often black and white. … If you want to make political progress it's a natural give and take,” Meijaard says. They modeled their paper on Jonathan Swift's “A Modest Proposal,” which suggested an ironic solution to poverty and population growth in 18th century Ireland: Eat the children. “Humor can reveal us as holding dual standards—as most of us do,” Sheil says. “Once you can laugh at your own viewpoint it's easier to step outside [it] and see how narrow-minded you've been.”

    Iberian Lynx Not Jinxed by Genetics


    A study of ancient DNA has given scientists more hope that the world's most endangered cat species can be salvaged. Habitat destruction and the decline of its main prey, the European rabbit, have caused the population of the Iberian lynx (Lynx pardinus) to plummet below 300 individuals in two isolated areas in Spain. Scientists are trying to help with a breeding program, but some believe a lack of genetic diversity—which leads to inbreeding problems and an inability to adapt to change—may doom the species. But a new study of DNA found in fossil bones shows that the Iberian lynx has had very low genetic diversity, and presumably small populations, for at least 50,000 years. For reasons that are unclear, it always got by, the researchers conclude in their paper in Molecular Ecology. If the lynx is lost, they say, don't blame its genes; blame the lack of political will to save it.

    By the Numbers

    8.7 million +/−1.3 million — Number of eukaryote species on Earth, including 6.5 million on land and 2.2 million in the oceans, according to a report by Census of Marine Life scientists in PLoS Biology.

    €239 million — Cost of unused H1N1 vaccines in Germany that are expired and being destroyed. Three-quarters of 34 million doses ordered went unused due to distribution problems and confusion over how many doses conferred protection.

  4. Paleoanthropology

    Who Were the Denisovans?

    1. Ann Gibbons

    At an unusual meeting at a Siberian cave, researchers find that these mysterious archaic humans lived in the same place as both modern humans and Neandertals—though not necessarily at the same time—and their range probably stretched into east Asia.

    Room with a view.

    Denisova Cave was such prime real estate, it attracted three kinds of humans.


    DENISOVA CAVE, SIBERIA—Bence Viola first saw the ancient molar last summer, just after a piece of it was dug out of layers full of brown dirt, gray rock, animal bones, stone tools, and goat feces. He considered the tooth fragments too big and weirdly shaped to be human. “I thought it must belong to a cave bear,” he says.

    Several fossils were found that summer in this remote cave in the Altai Mountains. Some, including a toe bone, looked human and were to be sent for DNA analysis to paleogeneticist Svante Pääbo at the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany. Viola, a postdoc at Max Planck, almost didn't include the molar. But he and Pääbo decided to play it safe and test all the new fossils. The layer that held the molar in Denisova Cave was also the resting place of a girl's finger bone, which was so well preserved that Pääbo's lab was able to sequence its nuclear genome and identify it as belonging to a previously unknown type of archaic human. The team called them the Denisovans. For the first time, researchers had a genome in search of a fossil record, so every possible new bone was significant.

    Cave treasure.

    Researchers have found the tooth of a Denisovan, plus a sophisticated stone bracelet and tools, in Denisova Cave.


    Back in Leipzig, graduate student Susanna Sawyer was charged with extracting DNA from the animal bones. In June, she stopped Pääbo in the hall. “I think I found another Denisovan,” she said. Preliminary analysis suggested that the molar's DNA was similar to that of the cave girl's. Pääbo shook Sawyer's hand—this was only the third fossil ever found of a Denisovan, the others being the bit of finger bone and another molar, also from Denisova cave.

    What's more, preliminary analysis of the mitochondrial DNA from the toe bone suggests that it belonged not to a Denisovan but to a Neandertal. That means both types of archaic humans lived in the same cave. And the large, three-room cave also holds sophisticated stone tools and bone artifacts that appear to have been crafted by our own species, Homo sapiens. “The one place where we are sure all three human forms have lived at one time or another is here in Denisova Cave,” Pääbo said.

    Today the cave is off the beaten path, in southern Siberia, 350 kilometers north of the Russian border with both Kazakhstan and Mongolia, and closer to Beijing than Moscow. Now the Denisovan discoveries have shifted the spotlight from ancient humans in Africa, the Middle East, and Europe to those in this remote corner of Asia. As Russian Academy of Sciences (RAS) archaeologist Anatoly Derevianko puts it: “The world is looking eastward.”

    Meeting of the minds.

    Archaeologist Anatoly Derevianko (top) and paleogeneticist Svante Pääbo worked together to discover the Denisovans.


    To that end, Derevianko and his Russian colleagues invited Pääbo and a select group of human origins researchers from different disciplines and countries to a remarkable symposium at an archaeological camp near Denisova Cave in July. Their goal was to try to solve the mystery of the cave girl's identity, to find more of her people, and to explore how the discovery is challenging models of modern human origins. In lively discussions sometimes catalyzed by vodka toasts, they compared what archaeology, genetics, and fossils reveal about the world the Denisovans inhabited 30,000 to 50,000 years ago. Genomic data have already shown that our ancestors mingled with archaic humans, who may have given us valuable immune cell types (see sidebar, p. 1086). But it's not clear when and where this happened.

    Invisible human

    The gathering gave Derevianko, director of the Institute of Archaeology and Ethnography at the RAS in Novosibirsk, a chance to showcase some of the region's impressive archaeological sites. Driving off dirt roads in troop movers and along rutted roads in indestructible UAZ vans, the Russians took their visitors to a dozen digs. Some were caves at the edge of alpine forests of silver birch and Siberian larch; others were open-air sites in grassy meadows of bee balm, wild mint, and edelweiss.

    The trail of ancient humans starts with H. erectus, which left primitive “pebble” tools in the Altai almost 800,000 years ago. After a hiatus when the climate was frigid, the descendants of H. erectus returned by 300,000 years ago, leaving more tools behind. Some kind of human has lived here ever since.

    Starting 80,000 to 70,000 years ago, archaic humans began to use more modern methods to make tools at sites called Kara Bom and Ust-Karakol, where 10% of the tools were blades or burins (a tool used to chisel wood); the Russians see this as the first stirrings of modern human behavior here.

    From 50,000 to 30,000 years ago, the archaic people hunted bear, lynx, and wild boar in the Altai Mountains, where they set up seasonal camps in summer, said RAS archaeologist Mikhail Shunkov as he led the tours. They retreated to limestone caves such as Denisova in winter. “With a natural opening for a chimney, the cave was quite a cozy place,” Shunkov said, pointing to an opening in the ceiling at Denisova. With a clear view of the Anui River—and any humans or animals passing below—Denisova must have been choice housing, said Pääbo, noting how sunlight streaming through the opening overhead lit the cave like a chapel. “It is kind of cool to imagine that the person whose genome was sequenced had seen these walls,” he said.


    At about this time, at least two different types or local cultures of artifacts appear, one at Kara Bom and one at Ust-Karakol. The Russians consider both to be sophisticated cultures traditionally associated with only H. sapiens. Similarly advanced artifacts appear at the same time in Denisova, with stone bladelets used on spears; pendants made of teeth of fox, bison, and deer; and even a bracelet made of a mineral found hundreds of kilometers away. Until recently, the archaeologists had “no doubts that people associated with this industry were anatomically modern,” Derevianko says. But now, thanks to the genomic results, it's possible that some were Denisovans, Shunkov says.

    To identify the toolmakers, researchers need fossils, but they are few and far between. As a result, “it remains unknown what the Denisovan looked like or how he behaved,” says biological anthropologist Maria Mednikova of the RAS in Moscow. So Viola's talk at the meeting, describing the single new tooth, drew intense interest. Like the first molar found, it is very large and lacks specialized features found in Neandertals. Nor does the tooth resemble a modern human molar, as it has many unusual cusps, Viola says. The finger bone fragment that first yielded Denisovan DNA was so small that it yielded little information other than it was a child's because the growth plate was not fused.

    In addition to the few Denisovan fossils, Neandertals also left fossils and characteristic Mousterian stone points and scrapers in Denisova and other caves. At the meeting, Russian researchers described new finds of Neandertal tools and fossils in caves just 100 and 150 kilometers away from Denisova Cave, dated to 45,000 years ago. Mednikova adds that the toe bone from Denisova looks most like a Neandertal toe from Iraq, fitting well with the preliminary DNA finding. And yet Derevianko thinks Neandertals didn't stay long here, because their bones and artifacts disappear by 40,000 years ago. He views them as brief visitors, probably coming from the west in Kazakhstan.

    Neighbors, or successors?

    It is now clear that Neandertals, Denisovans, and modern humans once occupied the Altai—but were they all there at the same time? This is hard to answer because there are questions about the dating of crucial layer 11 in Denisova Cave. This meter-thick layer held the Denisovan finger and molars, the Neandertal toe, and the modern human artifacts, although some were found in different galleries of the cave. The bones and teeth are too fragmentary to be dated directly. But radiocarbon dating of seven animal bones with cut marks from layer 11 provides dates of 50,000 years or older in both galleries. Yet the layer's youngest sediments date to as late as 16,000 to 30,000 years ago, as reported in December in Nature. Thus layer 11 has artifacts from at least two different periods. And, in the south gallery near the spot where the finger bone was found, an obvious wedge of disturbed sediment suggests some mixing.

    For now, Derevianko and colleagues propose sequential occupations: The Denisovans were in the cave about 50,000 years ago, Neandertals came in briefly about 45,000 years ago, and modern humans followed. But the researchers agree that the microstratigraphy of the cave needs more analysis. They are redating layer 11 with radiocarbon on more cut-marked animal bones.

    On tour.

    Archaeologist Mikhail Shunkov showcased the many archaeological sites of the Altai Mountains.


    Overall, Derevianko and his colleagues see a gradual, local evolution of H. erectus into H. sapiens in the Altai, with a brief intrusion of Neandertals and Denisovans. This fits a minority view of human origins, called multiregionalism, which posits that the descendants of H. erectus evolved into Neandertals and modern humans—and, apparently, Denisovans—in different regions. Then humans coming out of Africa mingled with the other groups and H. sapiens emerged worldwide.

    As Russian and Chinese archaeologists raised their glasses to toast regional continuity, however, several geneticists shifted uncomfortably or even quietly demurred: That theory is in contrast to the long-prevailing view that H. sapiens was born in Africa and swept the globe, wiping out local archaic peoples. And in light of the genomic data, most geneticists now hold a middle-of-the-road view that modern humans arose in and spread out of Africa, then interbred with local archaic peoples to a limited degree (Science, 28 January, p. 392). “If you write that I drank a toast to [regional] continuity, I'll kill you,” one geneticist told a reporter.

    But the geneticists do agree with the Russians that modern humans mingled with both Neandertals and Denisovans. Pääbo's team found in 2010 that living Europeans and Asians have inherited about 2.5% of their DNA from Neandertals (Science, 7 May 2010, pp. 680 and 710) and that living Melanesians carry an additional 5% of Denisovan DNA.

    If modern humans interbred with Neandertals, researchers speculated that fossils of each group, about the same age and found close to each other in Israeli caves, represented the groups who mixed sometime before 90,000 years ago. Those modern people carrying a small amount of Neandertal DNA then split into at least two groups—one that headed into Europe to replace the Neandertals there, and a second group that headed into Asia to mix with the Denisovans, says population geneticist David Reich of Harvard Medical School in Boston.

    At the meeting, the DNA researchers offered some new insights into this story. They found that the three Denisovans, all from one cave, had more variation in their mtDNA than did seven Neandertals from western Europe to Siberia, Sawyer reported. This and another report at the meeting—that Australian Aborigines, like Melanesians, have inherited 5% of their DNA from Denisovans—suggests that the Denisovan home range once stretched far beyond the Altai, into eastern Asia. “This tells us that the Denisovans had large population sizes,” despite their puny fossil record, Pääbo says. It also shows that Denisovans and the ancestors of Melanesians must have interbred before 40,000 to 60,000 years ago, when Aborigines first settled Australia.


    Anthropologist Maria Mednikova (top) analyzed fossils, and geneticists Susanna Sawyer and David Reich studied the DNA of the ancient Denisovans.


    As for the timing of the Neandertal-human mixing, the newest analyses tend to push that younger. Population geneticist Montgomery Slatkin of the University of California, Berkeley, said that his model runs gave him a wide range of preliminary results, from 65,000 years to 45,000 years ago, but he's still working the numbers. Reich reported that his independent analyses also suggest a younger date. If the mixing happened more recently than 90,000 years ago, it rules out the Israeli fossils as representatives of the groups who mixed.

    Others, such as Derevianko and paleoanthropologist John Hawks of the University of Wisconsin, Madison, interpret the genetic data differently. They think that even small amounts of interbreeding confirm the regional continuity model, and that there was more mixing in the past, but its traces were erased by later waves of immigrants who swamped out the archaic genes.

    To help decide among these models, several groups are searching for Denisovans beyond Denisova, as far east as China, where Pääbo is now analyzing fossil DNA. As Pääbo climbed down a ladder into a floodlit pit at Denisova and bent his lanky frame low to get a good look at layer 11, a colleague shouted: “Grab a trowel, Svante.” Pääbo didn't. But like the others, he is convinced that all types of data—genetic, archaeological, and fossil—will have to be integrated in order to tell the story of the Denisovans and so of our own species. “We're beginning to clarify history in eastern Eurasia,” Pääbo said, “and I'm sure that in the next few years, there will be more discoveries.”

  5. Paleoanthropology

    A Denisovan Legacy in the Immune System?

    1. Ann Gibbons

    A study published online in Science this week suggests that mating between human ancestors and other now-extinct groups boosted the immune systems of early Europeans and Asians.

    Everybody knows about the dangers of inbreeding (see Hapsburg dynasty, collapse of). In fact the reproductive strategies of many animals are based on avoiding it, as when female chimpanzees move out of their birth groups to mate. Last year, researchers showed that human ancestors took that strategy to its limits by breeding with the now-extinct Neandertals and Denisovans (Science, 28 January, p. 392). Now a study published online in Science this week ( suggests that such mating was beneficial, boosting the immune systems of early Europeans and Asians and leaving a valuable legacy in the genes of many people alive today. “This is the first suggestion that something that came from archaic hominins into modern humans conferred an advantage,” says paleogeneticist Svante Pääbo of the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany.

    Genomic data from fossils thus far suggest that living people carry only small amounts of archaic DNA. Only 2% to 7% of the DNA of today's Europeans and Asians apparently came from the ancient Denisovans and Neandertals (see main text). The new paper examines Europeans and Asians and finds that archaic people contributed more than half of the alleles that code for proteins made by the human leukocyte antigen system (HLA), which helps the immune system recognize pathogens. “Archaic alleles have significantly shaped modern human immune systems,” wrote Peter Parham and Laurent Abi-Rached of Stanford University in Palo Alto, California.

    Ancient roots.

    The allele HLA-B*73, today mostly seen in west Asia, may come from Denisovans.


    Immunogeneticist Parham has spent 16 years puzzling over the evolution of one rare HLA allele, called HLA-B*73. This variant is quite different from others but is similar to alleles in the same position in the genomes of chimps and gorillas. So it seems to be ancient, perhaps arising long before our ancestors split from gorillas about 16 million years ago. Yet today, B*73 is concentrated in western Asia, where modern humans have lived for less than 90,000 years, and it is absent from African tribes who usually carry the most ancient gene lineages.

    While studying this allele, Parham's team got a big break last year when Pääbo's team published the complete genome of the Denisovan cave girl. She didn't carry B*73—and it hasn't been found in Siberia—but she carried two other linked HLA-C variants, which occur on the same stretch of chromosome 6. If living people have any of these variants, they almost always carry at least two of the three variants—as did the cave girl. So even though she lacked B*73, the researchers propose that all three variants were inherited, often in pairs, from archaic humans in Asia. The Denisovans are the prime suspects, given their presumed distribution in Asia.

    The team also examined other HLA alleles in three Neandertals and one Denisovan and found several other ancient variants that today show up in living Asians or Europeans. Parham thinks these variants were beneficial and so, once acquired from archaic people, spread rapidly in small but expanding modern populations. “The fact [that these genes] may have been parachuted into modern humans is an attractive interpretation,” says immunologist John Trowsdale of the University of Cambridge in the United Kingdom.

    However, others are not quite convinced that the alleles came from archaic humans. Parham's team hasn't completely ruled out other explanations for the gene distributions, such as certain types of selection, says geneticist David Reich of Harvard University. Regardless, he says, “I am happy to see people using archaic genomes for different kinds of analyses.”

  6. Tissue Engineering

    Mending the Youngest Hearts

    1. Gretchen Vogel

    Researchers have begun implanting tissue-engineered blood vessels into toddlers with heart defects, and new studies of the grafts in animals show they work in unexpected ways.

    Biodegradable scaffold.

    Bone marrow cells seeded on a synthetic frame attract immune cells; these signal nearby vessels to grow into and over the graft.


    The notion that tissue engineers can provide a stock of lab-grown body parts to replace faulty tissues is still, for the most part, a dream. Ready-made hearts, livers, or kidneys that could ease the shortage of donor organs will not be available in the clinic anytime soon. But recent progress suggests the dream is not completely beyond reach. Lab-grown bladders are functioning in dozens of patients in the United States, and doctors in Europe have implanted lab-grown tracheas into several patients. In Japan, several dozen children and young adults born with severe heart defects are living with tissue-engineered cardiac blood vessels. The first received implants 10 years ago. They go to school, hold full-time jobs, play sports—in short, says Christopher Breuer, one of the implants' developers, they live active, healthy lives. This month, after an arduous approval process, surgeons are testing the blood vessels in the first U.S. patients.

    The U.S. trial marks “an important signpost for the whole field,” says Joseph Vacanti, a transplant surgeon and tissue engineer at Massachusetts General Hospital in Boston. The implants, which are used to connect a major cardiac vein and the artery that carries blood to the lungs, are made of a synthetic scaffold seeded with cells from the patient's own bone marrow. In the body, the graft develops into a living blood vessel that grows with the patient.

    The engineered vessels were developed by a group at Yale University led by Breuer, a pediatric surgeon, and Toshiharu Shinoka, a cardiosurgeon. Although getting approval for the trial from the U.S. Food and Drug Administration (FDA) took more than 4 years and generated more than 3000 pages of documents, the process paid off, Breuer says: Recent animal studies, arising in part from questions the FDA asked, have turned some of Breuer and Shinoka's assumptions upside down, leading to a better understanding of how the graft works and ideas for how to improve it.

    The new experiments suggest that inflammation, long seen as an enemy of transplants and artificial implants alike, seems to play a key role in the transformation of the cell-filled scaffold into a healthy blood vessel. And stem cells, which have been seen as the stars of tissue engineering, play a less significant role than expected. The results are prompting tissue engineers to rethink the role of inflammation and stem cells, says Anita Driessen-Mol, a tissue engineer at Eindhoven University of Technology in the Netherlands. “It's very inspiring work,” she says.

    Lifesaving implant.

    A graft bypasses the heart, redirecting low-oxygen blood from the inferior vena cava directly to the pulmonary artery.


    Replumbing the heart

    The lab-made blood vessels are meant for children whose severely malformed hearts are unable to supply their bodies with enough oxygen. At birth the children are known as “blue babies” for the skin tint that results. Unlike children with a normal heart, which has two blood-pumping chambers, or ventricles, these children have only one working ventricle. Without a repair, Breuer says, 70% of children with such defects will die before their first birthday.

    In the late 1960s, the surgeon Francis Fontan and his colleagues developed a technique to make such hearts more efficient. They rearranged the organ's plumbing to concentrate pumping in the single functioning ventricle. Over the years, surgeons have improved the procedure by adding a length of blood vessel to better connect the heart's inferior vena cava, which collects blood from veins in the lower body, to the pulmonary artery, which leads to the lungs, bypassing the heart (see diagram). In a few cases, surgeons can build this diversionary vessel from the patient's own tissue. But often there isn't enough tissue available, and surgeons use tubes of synthetic materials such as Gore-Tex.

    Such artificial blood vessels have significant drawbacks, Breuer says. The grafts can become calcified, trigger blood clots, and, if cells build up on the inside, can develop stenosis, a dangerous narrowing of the vessel. And because the synthetic graft doesn't grow with the child, surgeons must either delay surgery until the heart has grown larger or implant a graft that is initially too big.

    For more than a decade, Breuer and Shinoka have been working to develop lab-grown vessels that act like a patient's own tissue. The team uses a scaffold made of a biodegradable polyester tube, which they incubate briefly with a patient's bone marrow mononuclear cells (BMCs)—a mix of cells including immune cells and blood-and vessel-forming stem cells. Some of the patient's cells stick, seeding the scaffold.

    Preclinical experiments in lambs showed that the grafts soon formed a normal-looking blood vessel, with endothelial cells lining the inside and smooth muscle cells surrounding them. As expected, the scaffold degraded within a few months; new collagen fibrils, the connective tissue that helps blood vessels hold their shape, replaced it. And just like a normal blood vessel, the new tissue could grow. Based on those positive results, the clinical trial in Japan was approved and went ahead. Results have been very promising. The only complications were a few cases of stenosis, Shinoka and his colleagues have reported.

    Engineer surgeons.

    Shinoka (left) and Breuer launched a U.S. trial this month.


    Still, researchers weren't sure exactly how the new blood vessel formed. Were the seeded cells growing and differentiating? Or were new cells migrating into the graft? To better understand what happens after implantation—and to prove to the FDA “that each step of the way we were doing what we thought we were,” Breuer says, he and his colleagues went back to the lab. Using new, more precise fabrication techniques, they developed a mouse-sized version of their blood vessel scaffold. They seeded it with human BMCs and implanted the vessel in mice. To their surprise, though the vessel remained intact, the human cells disappeared within a week.

    To test whether the human cells disappeared because they were attacked by the mouse immune system, the researchers seeded a vessel scaffold with mouse cells genetically matched to the recipient but tagged with green fluorescent protein (GFP). In a paper in The FASEB Journal this month, they confirm their earlier results: A week after implantation, almost all of the GFP-tagged cells had disappeared.

    The observation “was a huge eye opener for the field,” Driessen-Mol says. “We thought that the cells you put in there would still be around for weeks.” Instead, it seems, the blood vessel that forms somehow comes from cells in the host's body. Although the seeded cells don't stick around for long, they do provide an advantage to the implant, the researchers reported last year in the Proceedings of the National Academy of Sciences. They secrete a protein that attracts monocytes, immune cells that modulate inflammation and can help prompt the formation of new blood vessels. Breuer's team showed that the seeded cells “are essential to initiate the proper kind of inflammation response. Somehow they attract the right kind of initial cells,” Driessen-Mol says.

    To pinpoint the origin of the cells that build the new blood vessel, the Yale researchers created special chimeric mice. They gave female mice a lethal dose of radiation to destroy the rodents' immune and blood-forming stem cells, then rescued the mice with bone marrow stem cells from males that carried the GFP gene. The donated cells repopulated the animals' bone marrow, and soon the female mice had GFP-tagged male cells in their blood.

    The researchers implanted their cell-seeded polyester tube into the chimeric mice and tracked what happened. In the first few weeks after implantation, the researchers found male, GFP-expressing immune cells in the grafts. But by 6 months, the endothelial cells and smooth muscle cells that formed the new stable blood vessel were all female. They also found no sign of stem cell markers in the vessel, suggesting that the cells growing into the graft were differentiated cells from the female host—not her stem cells at all. Further experiments with tagged cells showed that the new cells come from the adjacent blood vessels.

    Taken together, Breuer says, the evidence suggests that the graft prompts the adjacent vessels to expand into and over the implanted scaffold in a process similar to normal blood vessel growth. Robert Nerem, a tissue engineer at the Georgia Institute of Technology in Atlanta, says these experiments represent “exactly the kind of study that needs to be done so we understand what's happening mechanistically in these therapeutic approaches.” Still, he would like the results confirmed in larger animals.

    Engineered regeneration

    The results from these animal studies overturn the belief, held by many tissue engineers, that rare stem cells in the seeded BMCs would differentiate and grow on the implanted scaffold to form new tissue. The results are consistent with other evidence that BMCs can prompt tissue repair without contributing to the new tissue directly; something similar seems to happen when the cells are injected into diseased hearts. Breuer says that a more precise understanding may help researchers design safer and more effective lab-grown tissues. He and Shinoka are working to develop grafts that wouldn't need seeded cells but instead would contain a combination of signaling molecules to attract the needed response from monocytes.

    That could make the implants easier to produce and much less expensive, Vacanti says, increasing the chance that they would be widely adopted. He says the new understanding might also simplify efforts to construct the tissue engineer's ultimate challenge: whole organs, with multiple cell types and a full set of blood vessels. For researchers trying to construct entire hearts, for example, “you could imagine that you wouldn't need to preseed with vascular cells, just with muscle cells,” he says.

    In the meantime, the new trial will track the six U.S. patients after they receive their implants, following up with regular magnetic resonance imaging scans to watch for signs of stenosis. The team proposed starting small, Breuer says, to signal to the FDA that “we're willing to get started very slowly and carefully.” That's the right approach, Vacanti says. “It's terrific that they are going ahead,” he says. “Their work is thoughtful, rigorous, and very carefully done.” Setting a positive precedent is crucial for the field, he says. “They'll do it properly.”

  7. European Universities

    Europe's Innovation Engine, Eager to Grow, Faces Criticism

    1. Colin Macilwain*

    A European attempt to remain competitive by boosting innovation is off to a shaky start.

    Ready for the future?

    Europe's leaders fret that their high-tech industries are slow to innovate.


    When José Manuel Barroso, the president of the European Commission, first suggested building the European Institute of Technology (EIT) in 2005, perhaps to rival the Massachusetts Institute of Technology on the global stage, he got a skeptical response. Many argued that existing universities would be better placed than a new institute to bolster Europe's competitiveness.

    The result was a fudge. EIT was indeed established—and slightly rebranded as the European Institute of Innovation and Technology— but rather than a brick-and-mortar institute, it became a network of dozens of universities and companies across Europe with a small headquarters in Budapest. Its budget was just €309 million over the period 2007–13.

    Now, the European Union is considering a major expansion of EIT, which in June issued a strategic plan that would cost €4 billion over the next budget round, from 2014 to 2020. But the young institute is beset by problems. A scathing external review has criticized its track record, universities say they feel out of the loop about its targets and activities, and industry appears divided on its usefulness and reluctant to pay its share of the bill. Managing the institute has been complicated by the rapid turnover of senior staff.

    EIT was meant to give Europe a leg up in the innovation competition with countries such as the United States, India, and China. “Europe is struggling with innovation by any measure,” says Martin Schuurmans, former executive vice president of Philips Research, the research arm of the Dutch electronics corporation, and the first chair of the EIT board. “We have been spending billions on R&D programs, and these have helped, but we are still struggling, and we need new approaches.”

    EIT's approach seeks to reinforce all three sides of the so-called innovation triangle of business, education, and research through newly created consortia of universities and companies across Europe known as Knowledge and Innovation Communities (KICs). The first three KICs—dealing with climate change, information technology, and energy—have been established over the past year, and up to a dozen more could follow.

    The KICs receive funding to train graduate students in science, technology, and business; conduct collaborative research; and cultivate new high-tech companies. Each distributes its work among half a dozen “co-location centers” hosted by a university partner (see sidebar).

    But the way EIT's governing board has set up the first three KICs has rankled European universities that are meant to be its partners. “There is huge frustration from these universities, including those who are participating and those who are not,” over EIT's failure to consult with them, says Karin Markides, president of the Conference of European Schools for Advanced Engineering Education and Research (CESAER). She says EIT's strategic plan is vague as well. “Most of us really believe in this concept,” Markides says, “but it has been described in far too general a way.”

    The external review, undertaken by consulting company Ecorys for the European Commission and released in June, echoed CESAER's criticism. It said EIT “has not yet engaged extensively with the wider audience of organisations involved in promoting innovation within the E.U.” and criticized the Budapest headquarters for its subservience to EIT's governing board.

    But the board says it was essential to forge ahead with the KICs. “The European style is just to keep talking, but we have had to make choices. There will always be people who see things differently,” Schuurmans says. “The European Union discussed this idea for 4 years—and we implemented it in 18 months.” Now the KICs need the time to show what they can do, he says.

    Rooted in the past

    The KICs' first concrete actions have been in education, for which the ambition is to combine science or engineering with the kind of dynamic entrepreneurship associated with Silicon Valley or the greater Boston area. Each of the KICs is planning distinctive master's and Ph.D. programs; students will spend time at universities in at least two nations, learn business skills, and work in industry.

    So far, interest seems high. For instance, the KIC InnoEnergy has received 900 applications for the first 200 master's places, which start next month, says Chief Executive Officer Diego Pavia, an electrical engineer with a background in the computer industry.

    And even EIT critics agree that this kind of course is needed in Europe, where few postgraduate degrees in science or engineering include business training. “I'm pretty convinced that what they are doing in education will add value,” says Peter Tindemans, chair of the policy committee at the lobby group Euroscience and a longtime skeptic about EIT's organization model.

    It's not clear whether industry is equally interested. Rolls-Royce and Philips, two of the three major companies to comment on a European Commission consultation exercise on EIT this spring, were lukewarm in their public submissions. A third—Cambridge-based chipmaker ARM, one of Europe's most striking high-tech success stories—said the effectiveness of EIT was “destined to be greatly disappointing,” arguing that its co-location model was “impossible” and “unnecessary” in a world in which research partners no longer need to be close together to collaborate. “Their implementation is rooted in the past,” ARM's principal engineer, Ian Phillips, told Science.

    Industry is supposed to help finance EIT's activities. The KICs' multiyear business plans state that 25% of funding will come from EIT, about 25% from private sources, and the rest from other public sources, including regional, national, and E.U.-wide research programs. The hope is that companies will be attracted by the pool of research expertise and student talent at the co-location centers.

    Schuurmans and other EIT leaders declined to estimate the total current value of corporate pledges, saying that it was “too early to say.” But Pavia says he's confident that his energy KIC will have no trouble meeting its target of getting 26% of its income from the 34 companies involved.

    Traumatic negotiations

    Meanwhile, critics say the rapid personnel changes at EIT signal an organization in turmoil. Jan van der Eijk, the first chief executive of the climate KIC and a former chief technology officer of Shell, left last December, after just 6 months on the job, amid tough negotiations to constitute the KIC. The first director of EIT, Gérard de Nazelle, left last September after 12 months in the position. His successor, Spanish space technologist José Manuel Leceta, didn't start until July.

    Supporters and critics agree on one thing: If EIT is to have any noticeable impact on European innovation, it will have to markedly expand. In June, the European Commission said it hopes to secure €80 billion for Horizon 2020, the 7-year research and innovation program starting in 2014. The EIT governing board has asked for a €4 billion slice of that pie; one European Parliament source says the number in the European Commission's budget proposal, due later this year, may be closer to €2 billion. “If they just double funding [to €600 million], they should close it tomorrow,” says Willem Jonker, who heads ICT Labs, the information technology KIC.

    The decision will depend in part on E.U. member states and the European Parliament. Although initially skeptical, countries are now warming to EIT, says Maria da Silva Carvalho, a Portuguese member of the European Parliament who, as an adviser to Barroso, played a key role in devising EIT's structure. “It's not an easy model to set up, but what has been established is a good basis, and we have top universities and companies involved.”

    Pavia says Europe has no choice but to continue the experiment if it is serious about staying competitive. “This is the only way European innovation can make a breakthrough,” he says. “Otherwise, in 20 years' time, we will just be living in a theme park.”

    • * Colin Macilwain is a writer in Edinburgh, U.K.

  8. European Universities

    Can These Networks KIC-Start European Innovation?



    The Knowledge and Innovation Community (KIC) called InnoEnergy, dedicated to sustainable energy sources, is distributed over six co-location centers focusing on nuclear energy, renewables, energy efficiency, clean coal, “smart grids,” and energy from chemical fuels. The network will receive €30 million from the European Institute of Technology this year and €80 million from its partners, which include 11 universities and 34 energy companies, including major ones such as Sweden's ABB. “In budgetary terms, [industry's] contribution doesn't go above 26%—but in terms of its real value, we're getting billions of euros,” says the KIC's chief executive officer, Diego Pavia.



    The Climate KIC will develop approaches to counteract climate change, such as smarter energy and water distribution systems. That means it will serve a young industry with few well-established players. University partners include elite institutions such as ETH Zurich and Imperial College London; among the five corporate participants are energy supplier EDF and Amsterdam's Schiphol Airport. Because publicly funded organizations play such a prominent role in responding to climate change, the KIC also has public partners, says Chief Executive Mary Ritter, including the Dutch province of Utrecht, which is hosting a pilot project on climate-resilient, low-carbon cities.

    Information and Communication Technology


    ICT Labs has perhaps the broadest of all of the KICs' remits, dealing with what European policymakers regard as the continent's persistent failure to compete effectively with the United States in information technology. The consortium includes 21 universities, six research centers, and 20 companies, including household names such as Siemens, Philips, Nokia, and Ericsson. Chief Executive Officer Willem Jonker says that it'll be previous advances in ICT itself—such as Skype conferencing—that will enable the KIC to operate as a single unit. “Twenty years ago it would not have been possible,” he says.

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