EDITORIAL T oday, the relationship between biological research and animal testing is being challenged by numerous groups and individuals, who claim such experiments are in breach of animal welfare. In fact, animal research, which is necessary for scientific progress, can and must be conducted in keeping with the principles of veterinary medical ethics. Today’s climate of propaganda and obscurantism calls for clarification. The mission of biological research is to investigate life: its origins, diversity and evolution, the organization of molecules, cells, organisms and populations, and the genetic, physiological, and environmental factors that govern its vast complexity. Fulfilling that mission requires to observe life forms of all types, and act upon them to determine how they work. Animal research is essential for understanding the “rules” of living beings—even when these rules have first been approached in vitro or in silico. An outright ban on animal testing would seriously hinder biomedical breakthroughs, responses to biodiversity and environmental challenges, as well as the advancement of knowledge, all of which are scientific duties owed to the populations of enlightened countries. Research in human health is enriched by comparing data from animal experiments with results from the analysis of human pathologies. The discovery of “mirror” neurons in monkeys made it possible to understand how our brains can perceive the emotions of others, fundamentally altering our approach to autism and schizophrenia. Experiments on monkeys have also led to the development of prostheses that, in the near future, will be thought-controlled. The study of electric fish and aplysia has shed light on certain mechanisms involved in human visual memory. In any event, we must take our fellow citizens’ reservations about animal experimentation into consideration. Their objections arise from increasing awareness that animals are sentient beings that must not be made to suffer. Yet public opinion is oblivious to the fact that ethical issues are central to animal research, which complies with strict regulations to ensure animal welfare and integrity. At this stage, biology cannot do away with animal experimentation. Researchers must reassure the general public that animals used in laboratories are treated with respect—for the sake of future scientific progress. INTERNATIONAL MAGAZINE Trimestriel-Printemps 2015 Editorial Offices: 3, rue Michel Ange / F-75794 Paris cedex 16 Phone: +33 (0)1 44 96 53 88 Email: cnrs-magazine@cnrs-dir.fr Website: www.cnrs.fr CNRS (headquarters): 3, rue Michel Ange / F-75794 Paris cedex 16 Publisher: Alain Fuchs Editorial Director: Brigitte Perucca Deputy Editorial Director: Fabrice Impériali Editor: Saman Musacchio Production Manager: Laurence Winter Writers: Nicolas Baker, Laure Cailloce, Gabriel Chardin, Emmanuelle Crane, Marin Dacos, Eddy Delcher, Léa Galanopoulo, Arby Gharibian, Valerie Herczeg, Fabrice Impériali, Brett Kraabel, Fui Lee Luk, Saman Musacchio, Emma Walton Translation Manager: Valerie Herczeg Copy Editors: Saman Musacchio and Valerie Herczeg Graphic Design: Céline Hein Iconography: Anne-Emmanuelle Hery and Marie Mabrouk Photoengraving: Scoop Communication / F- 45160 Olivet Printing: Groupe Morault, Imprimerie de Compiègne – 2, avenue Berthelot – Zac de Mercières – BP 60524 – 60205 Compiègne Cedex ISSN 1778-1442 AIP 0001308 CNRS Photos are available at: phototheque@cnrs.fr ; http://phototheque.cnrs.fr All rights reserved. Partial or full reproduction of articles or illustrations is strictly prohibited without prior written permission from the CNRS. “Animal research is essential for understanding the ‘rules’ of living beings.” © DÉLÉGATION PMA By Catherine Jessus, Director of the CNRS Institute of Biological Sciences (INSB) On this cover: Camp of Pétionville in Port-au-Prince (Haiti), set up after the 2010 earthquake. © P. GORRIZ/UN PHOTO 3 SPRING 2015 N° 37 CONTENTS IN DEPTH 18 FEATURE I Animal Testing under Scrutiny . 18 PROFILE I Thomas Ebbesen: Shedding Light on Light . 24 PORTFOLIO I Touching the Depths. 26 SPECIAL REPORT I Permafrost, a Ticking Time Bomb . 32 © L. CAILLOCE/CNRS PHOTOTHÈQUE IN THE SPOTLIGHT 5 Cooperation with India, ESOF 2016, ERC Grants . 5 SCIENCE AT WORK 6 FOCUS I A World within a World . 6 LAB WATCH I Stop the Screech . 8 Gone with the Smell of Roses . 8 Hippos Boast New Ancestor . 9 Putting the LEDs back in Laser . 10 Assessing Nanopollution . 10 Avoiding Unnecessary Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . 11 Rising from the Ashes . 12 Karnak Yields more Treasures . 13 Mending Brittle Bones . 14 The Early Universe in Focus . 14 Biopsy-free Skin Cancer Diagnosis . 15 A Vote of Confidence for the LORIA . 15 OPINION I Fermi’s Paradox and the Missing Aliens . 16 Science in the Age of Open Access . 17 WORLDWIDE 38 PARTNERSHIP I LIMMS: Going Small, Thinking Big . 38 NEWSWIRE I Future Earth, a Program for the Planet . 40 Tunisia: Forty Years and Going Strong . 41 International Agreements . 42 CLOSE-UP 43 A Good Pitch . 43 13 © J. MAUCOR/CNRS-CFEETK Karnak Yields More Treasures The Early Universe in Focus © ESA/PLANCK COLLABORATION 14 Forty Years and Going Strong 41 © PIXEL DRONE TECHNOLOGIES This pictogram indicates that additional photographs can be accessed on the online version of the magazine www.cnrs.fr/cnrsmagazine 4 CNRS INTERNATIONAL MAGAZINE CNRS INTERNATIONAL MAGAZINE SCIENCE AT WORK LAB WATCH 8 Applied Physics BY BRETT KRAABEL Stop the Screech There is no mistaking the screech of adhesive tape being removed from a substrate. This sound in fact indicates an instability in the peeling process that not only damages the adhesive, but also produces unacceptable noise levels in industry. In medical applications, this instability can cause pain or even additional injuries when removing bandages. To help the adhesive industry overcome this problem, researchers from three CNRS laboratories 1 have conducted an extensive study2 with the support of the French National Research Agency (ANR). They analyzed how the speed and angle at which tape is peeled from its substrate affects stability, and found that the latter significantly decreases at large peeling angles. The resulting instability is called “stick-slip instability,” where the speed at which the strip separates from the substrate alternates rapidly between fast and slow. The precise characteristics of this instability, explains co-author of the study Marie-Julie Dalbe, “depend on factors such as the velocity applied to the free end of the ribbon, the properties of the glue, the elasticity of the tape, its inertia, and the angle of separation.” By using a custom-made device Illustration showing how different peeling angles (top) cause stick-slip instability in the tape (bottom). 1. Laboratoire de physique (ENS de Lyon / CNRS / Université de Lyon); Institut lumière matière (CNRS / Université Claude Bernard Lyon-I); Laboratoire Fluides, automatique et systèmes thermiques (CNRS / Université Paris-Sud). 2. M.-J. Dalbe et al., “Peeling-angle dependence of the stick-slip instability during adhesive tape peeling ,” Soft Matter, 2014. 10 (48): 9637–43. Plant Biology Gone with the Smell of Roses BY LÉA GALANOPOULO Customers in florist shops tend to agree: roses seem to have lost their scent. “By only selecting blooms that can survive longer than ten days in a vase, the world’s most popular cut flower has lost its fragrance,” explains Jean-Claude Caissard.1 Like other scientists, this plant biology specialist has been trying to solve the mystery of roses. “The Romans were the first to domesticate them,” he explains, “but this practice was abandoned during the Middle Ages, when roses were only used for their pharmaceutical properties.” However, in the 19th century, with the advent of the English garden, they were all the rage in France. “Growers therefore bred new varieties to meet increasing demand,” points out Blandine Veith,2 a sociologist specialized in the commoditization and patrimonialization of ornamental plants. There are now more than 30,000 rose varieties: “Breeders try to obtain blossoms that are increasingly large and colorful, on plants that can flower all year round,” adds Caissard. “In nature, however, a rose only blooms one or two weeks a year.” Yet hybridization is not the only culprit in this loss of perfume, which has always been a fragile trait. “Among the descendants of a specific rose line, 90% will not have the scent of their parents. In 10% of cases, the rose will keep a fragrance, but not necessarily the desired one: some may smell of pineapple, for example,” says the researcher who, with his team, has set out to map the genes that give roses their scent. “Fragrant roses sometimes have fragile petals, which makes them difficult to ship by air,” explains Veith. © J.-C. CAISSARD The scent of roses is an extremely fragile trait that is difficult to preserve from one flower to another. 1. Laboratoire de biotechnologies végétales appliquées aux plantes aromatiques et médicinales (Université Jean Monnet). 2. Laboratoire dynamiques sociales et recomposition des espaces (CNRS / Université Paris Ouest). 9 to peel the adhesive at constant speed, constant angle, and with a constant length of free tape, the researchers found three ways in which the strip separates from its substrate: stable separation, whereby the tape peels at constant speed; stick-slip separation; and bistable state, where stick-slip and stable separations alternate. Each of these dynamics occurs only at certain angles and separation speeds. Of industrial interest is stable separation, which the study shows to happen not only at low speeds and large angles, but also at high speeds and large angles. To elucidate the screech of peeling tape, Dalbe and colleagues are already investigating the connection between the noise produced and the stick-slip instability. The results should be of great interest to the many industries that work with adhesive tape. ii In a context of massive commoditization, the rose trade has indeed become international. South America and East Africa are home to most of the world’s largest rose farms, whose only focus is profitability. Their flowers ultimately flood the florist shops in the northern hemisphere, which leads to the marketing of only two types of cultivars, says Veith. Mass distribution could therefore cause loss of diversity in commercial varieties. To reverse this trend, some growers have decided to help bring old, highly scented roses back into fashion. And most breeders, aware that scent is important to customers, are seeking to return fragrance to the types of roses currently available. Meanwhile, they also experiment with extraordinary scents, including parsley, aniseed, and more surprisingly, red wine. ii Hippos Boast New Ancestor BY EMMANUELLE CRANE Paleontology mariejulie.dalbe@ens-lyon.fr Family ancestry is always somewhat of a mystery, regardless of the species, but this is especially true in the case of hippopotamuses. Yet a joint French-Kenyan team has now solved the enigma. Researchers at ISEM1 and IPHEP,2 working in collaboration with the National Museums of Kenya, recently discovered a fossil that bridges the evolutionary gap between hippos and the common ancestor they share with cetaceans. This finding, published last February,3 also shows that the ancestors of hippos were among the most ancient mammals to colonize the African continent some 35 million years ago, long before large carnivores, giraffes, and bovids. Geneticists, using DNA comparisons, had highlighted the close relationship between hippos and cetaceans back in the 1990s and 2000s, but there were no fossils documenting hippo ancestry. The fossil species recently discovered in Lokone (Kenya) confirms an evolutionary scenario congruent with genetic data. Epirigenys Iokonensis (“epiri” means “hippo” in the Turkana language) forms a transition between hippos and a lineage of anthracotheres, a now extinct ungulate family. The interdisciplinary collaboration between geneticists and paleontologists is proving fruitful. While the fossils enabled paleontologists to determine precise dates and trace the evolutionary process, geneticists demonstrate wellestablished relationships between living organisms. “Now we want to understand whether hippo ancestors had an aquatic life or a purely terrestrial one,” says CNRS researcher Jean-Renaud Boisserie of the IPHEP. This would bring scientists closer to understanding the evolution of the group. The next step for the team is to go back in time some 40-55 million years, prior to the emergence of anthracotheres. “New discoveries of fossils will be decisive to shed light on the common origin of hippos and cetaceans,” Boisserie concludes. ii © M.-J. DALBE/ILM, UNIV. LYON Left to right: evolution of a molar of Anthracotherium; Epirigenys; and primitive hippoppotamus. 40 million years ago 28 million years ago 10 million years ago © J.-R. BOISSERIE/LPRP jean.renaud.boisserie@univ-poitiers.fr bveith@u-paris10.fr jean.claude.caissard@univ-st-etienne.fr 1. Institut des sciences de l’évolution de Montpellier (Université de Montpellier-II / CNRS / IRD). 2. Institut de paléoprimatologie et paléontologie humaine: évolution et paléoenvironnements (Université de Poitiers / CNRS). 3. F. Lihoreau et al., “ Hippos stem from the longest sequence of terrestrial cetardiodactyl evolution in Africa,” Nature, 2015. 6:6264. 10 Optics Putting the LEDs back in Laser BY EDDY DELCHER Inside the pumping module are the crystal and the LEDs (not visible), cooled by water (red and blue cables). © A. BARBET/LCFIO 1. Laboratoire Charles Fabry (CNRS / Institut d’Optique Graduate School / Université Paris-XI). 2. A. Barbet et al., “Revisiting of LED pumped bulk laser: first demonstration of Nd:YVO4 LED pumped laser,” Optics Letters, 2014. 39(23): 6731-4. A joint research team involving the LCF1 and the specialized company EFFILUX has developed a solid-state laser amplified by light emitting diodes (LEDs), a cheaper and more reliable alternative to laser diodes.2 Solid-state lasers, which use a solid as gain medium (as opposed to gas or liquid in other laser types), are found notably in laser pointers and used for cutting and welding. They conventionally work by flashing light into a crystalline rod to inject energy into it in the form of photons, a process known as “pumping.” As the atoms in the rod soak up these photons, they get into an excited state, releasing the extra energy as a new photon. This new particle travels up and down the rod at the speed of light until it collides with another excited atom, causing it to release not one, but two photons. These continue to bounce up and down until they escape the rod through a tiny aperture, forming a concentrated light beam. Since the 1980s, the pumping at the heart of the system was performed by laser diodes—the ones Environment Assessing Nanopollution BY EDDY DELCHER A team involving researchers from the CIRIMAT,1 the LAAS,2 and the EcoLab3 have devised a new method to assess carbon nanotube (CNT) pollution in the environment.4 Extremely light, strong, and displaying electrical properties, CNTs are nearly ubiquitous in the manufacturing of a large number of products, such as cars, electronic components, and sports equipment. But their increasing prevalence has raised concern that some might be accidentally released in the environment during production or use. While it is possible to assess rejected amounts in small samples and within the confines of a laboratory, accurate readings in nature are far more complicated given the high quantities of carbon already present in the environment. The scientists based their research on amphibian larvae, the animals most affected by water pollution. By measuring their electrical permittivity, that is, the resistance encountered when an electric field passes through a medium, the researchers were able to determine the quantity of CNTs present in the samples. “We first measured the permittivity of CNTs alone, and of non-exposed larvae as references. We then checked that of larvae exposed to CNTs and compared it with the previous results. The difference between the two gave us a direct indication of the quantity absorbed,” explains Emmanuel Flahaut, who led the research. “Following exposure, the larvae quickly release the CNTs from their body. Now we have a tool to assess how long it takes to flush them out completely,” concludes Flahaut. This technique could be used to measure the quantity of CNTs in other complex environmental samples, such as contaminated soils or plants. ii 1. Centre inter-universitaire de recherche et d’ingénierie des matériaux (CNRS / Université Toulouse-III / INP Toulouse). 2. Laboratoire d’analyse et d’architecture des systèmes (CNRS). 3. Laboratoire écologie fonctionnelle et environnement (CNRS / Université Toulouse-III / INP-ENSAT). 4. E. Flahaut et al., “Quantitative detection of carbon nanotubes in biological samples by an original method based on microwave permittivity measurements,” Carbon, 2015. 81: 535 –545. flahaut@chimie.ups-tlse.fr found in barcode readers, CD/DVD players, and laser pointers, for example— which were much more powerful at the time than light emitting diodes (LEDs). However, recent advances allowed the researchers to develop a novel light amplification technique by wedging a crystal between two LED panels—a system powerful enough to create a laser. “While the beam is not as strong as with laser diodes, which are still ahead in terms of power, our intent was primarily to show that it is now possible to use LEDs,” explains Adrien Barbet, who conducted the research. Apart from being cheaper and more durable, LEDs are also far more powerful than laser diodes for pumping light in the visible part of the spectrum. “This means our system could soon find applications in industry, such as material processing and sensing, as well as in telemetry and remote sensing,” he adds. ii Molecular Oncology Avoiding Unnecessary Chemotherapy BY EMMA WALTON R esearchers led by Geneviève Almouzni1 at the Institut Curie have discovered a new prognostic marker of breast cancer2 that may help physicians determine which patients actually need chemotherapy, while sparing others unnecessary treatment. Following local surgery and/or radiotherapy, physicians must decide whether patients should receive chemotherapy to reduce the risk of recurrence. “This decision is based on criteria such as age, tumor size, grade, and hormone receptor status,” explains Zachary Gurard-Levin, a lead author of the study. “Yet these factors, along with DNA mutations, are not the only ones to influence pathology evolution,” Gurard-Levin stresses. “Cancer is also driven by ‘epigenetic’ alterations that affect how the DNA is ‘read’ without changing its sequence, and that ultimately determine which genes are switched on or off.” Working with the Institut Curie hospital, Almouzni’s team analyzed gene expression in tumors from 1127 breast cancer patients, focusing on epigenetic factors. “We identified certain epigenetic regulatory genes, the histone chaperone HJURP for example, that were highly expressed in some breast cancer subtypes, including the ‘luminal B’ type, but not the ‘luminal A’ type,” says Gurard-Levin. It is important to distinguish these two types of breast cancer as their clinical profiles are very similar, but their responses to chemotherapy differ. Yet current markers used to differentiate them are inadequate. The new findings, validated in an independent cohort of 71 patients, now provide physicians with a new biomarker to identify these subtypes. “Still, the most exciting result involves the histone chaperone HJURP,” says Gurard-Levin. “This is the first biomarker that can determine whether luminal A subtype patients have a good or poor prognosis. Clinical use of this epigenetic factor should help doctors predict the risk of recurrence more accurately.” Hopefully, such tests will ensure that chemotherapy is only administered to those who really need it. ii The histone chaperone HJURP helps differentiate between luminal A and B breast carcinoma. Luminal A adrien.barbet@institutoptique.fr © E. GURARD-LEVIN/CNRS/INSTITUT CURIE © C. SARRIEU, E. FLAHAUT, L. GAUTHIER/CNRS PHOTOHÈQUE/CIRIMAT/ECOLAB Luminal B CNT pollution is measured using Xenopus larvae. genevieve.almouzni@curie.fr zachary.gurard-levin@curie.fr 1. Director of the Laboratoire dynamique du noyau (CNRS / Institut Curie) and of the Centre de Recherche de l’Institut Curie. 2. Z. Gurard-Levin et al., “The histone chaperone HJURP is a new independent prognostic marker for luminal A breast carcinoma,” Molecular Oncology, 2015. 9(3): 657-74. Rising from the Ashes BY VALERIE HERCZEG Archaeology. New X-ray technique reads through rolled-up scrolls, bringing ancient literature to life. Detail of the carbonized papyrus scroll PHerc.Paris.4. Using a new X-ray imaging technique, an international collaboration1 including researchers from the IRHT2 succeeded in revealing some of the contents of two charred papyrus scrolls without unrolling them. Buried by the eruption of Vesuvius in 79 AD, the rolls of parchment were part of a library uncovered in Herculaneum’s so-called “Villa of the Papyri” in the mid-18th century. Preserved by thick layers of volcanic material, hundreds of them have survived to this day, although their extreme brittleness prevents them from being opened unharmed. Phase-contrast imaging While previous attempts to decipher rolled-up manuscripts using conventional X-rays proved unsuccessful,3 X-ray phase-contrast tomography (XPCT) enabled this breakthrough. The experiment was conducted at the Grenoble synchrotron (ESRF), the only such facility in Europe that can achieve the high energy levels required to obtain sufficient image quality for that purpose. Based on refractive index variation, the XPCT technology makes it possible to distinguish between the carbonized paper and the carbonbased ink obtained from smoke residues that was used in antiquity, notwithstanding their similar densities. In addition, XPCT exploits the fact that the ink does not penetrate into the papyrus fibers and stands in very slight relief (a few hundred microns) to amplify this contrast and highlight the letters. The researchers could therefore read words and characters buried under several layers of paper. After years of research on the Herculaneum scrolls, papyrologist Daniel Delattre, CNRS senior researcher emeritus at the IRHT and co-author of the study,4 was confident that “the fast pace of technological progress would lead to satisfactory results sooner or later.” So satisfactory, in fact, that the researchers were able to date one of the two papyri—from a collection of six presented as a gift to Napoleon in 1802 and kept at the Institut de France— to around 50 BC. The team also identified Epicurean philosopher Philodemus as its likely author. “This was an emotional 2000-year leap back in time,” all the more so as there exist no copies of these texts, the scientist points out. Looking to the future This discovery could eventually lead to deciphering the Herculaneum scrolls that remain intact, the others having been damaged by repeated attempts to unroll them over the past three centuries—often with disastrous results. Yet this is still some way away. “We must improve the legibility of letters, which is far from optimal at this stage, as well as try and automate the analysis and processing of thousands of images reconstructed from scans,” the papyrologist says. In addition, the internal spiral structure of the scrolls— deformed, entangled, and sometimes stuck together by the pressure of the pyroclastic flow —makes the researchers’ undertaking even more challenging. Enhanced Digital Unwrapping for Conservation and Exploration (EDUCE), a software developed in 2006 at the University of Kentucky (Lexington, US) to flatten and unroll papyri digitally, is being improved in the hope that it can be used successfully on the Herculaneum scrolls. Meanwhile, the “Villa of the Papyri,” antiquity’s only surviving library, may keep its secrets a little longer. Yet “it is early days,” notes Delattre, who trusts the charred manuscripts will eventually provide a better insight into ancient Greek literature and philosophy. Frozen in time for the past 2000 years, their message, it seems, is about to reach us. ii dandelattre@nordnet.fr brun.emmanuel@gmail.com © CNRS-IRHT UPR 841/ESRF/CNR-IMM UNITÉ DE NAPLES © E. BRUN Volume rendition of the reconstructed papyrus, which highlights the huge complexity inside the scroll, PYROCLASTIC FLOW fast-moving current of hot gas, ash and rock resulting from the eruption of a volcano. 1. CNRS / Consiglio Nazionale delle Ricerche / Ludwig Maximilians Universität / ESRF. 2. Institut de recherche et d’histoire des textes, Section de papyrologie (CNRS). 3. This work follows previous research carried out by W. B. Seales (University of Kentucky, US) and Daniel Delattre of the IRHT. 4. V. Mocella et al.,”Revealing letters in rolled Herculaneum papyri by X-ray phase-contrast imaging,” Nature Communications, 2015. 6(1): 5895. Karnak Yields more Treasures Archaeology. The Egyptian site of Karnak has produced some of the most spectacular finds in the history of archaelogy. And its riches seem infinite. BY VALERIE HERCZEG Small statue head, probably representing the god Imhotep. Two hundred years after excavations began, Karnak, near Luxor, has not revealed all its secrets. The recent search of a repository pit, or favissa, discovered last December near the temple of Ptah, yielded 38 statues, statuettes, and precious artifacts. These objects were brought to light by archaeologists from the French-Egyptian Center for the Study of Karnak Temples (CFEETK),1 as part of an interdisciplinary program2 aimed at studying the evolution of the temple and its surrounding area over the millennia. “The size and optimal state of conservation of the collection make this find exceptional,” explains Christophe Thiers, co-director of the CFEETK. Made of limestone, copper alloy, greywacke,3 and Egyptian faience,4 the artifacts are thought to have belonged to the temple of Ptah, built under Thutmose III (ca. 1450 BC), even though ceramic and hieroglyphic inscriptions show they are more recent (8th-7th century BC). Dedicated to the god Ptah, patron of artisans, they may have been damaged or removed over time and stored outside the building. No less outstanding is the recording technique used for the first time by researchers in a favissa containing statues. By compiling hundreds of photographs taken during the dig, the team obtained a 3D reconstruction of the excavation process, which they then linked, on the millimeter scale, with topographical reference points. This enabled them to assemble videos and “keep a record of the layout of the objects before they were removed from the site,” says Guillaume Charloux, archaeologist at the CFEETK. “This chance discovery sheds new light on worship practices at a given period in the history of the temple of Ptah,” says Thiers. “Meanwhile, we will pursue our objective to find out more about its influence, use, and successive layouts since its origins.” ii 40 cm © PHOTOS: J. MAUCOR/CNRS-CFEETK Statuette and figurine of the god Osiris, found outside the temple of Ptah. christophe.thiers@univ-montp3.fr guillaume.charloux@cnrs.fr 1. Centre franco-égyptien d’étude des temples de Karnak (CNRS / Ministry for Egyptian Antiquities). 2. IA-ANR-11-LABX-0032-01 (CNRS / Université Montpellier-III / Université de Perpignan Via Domitia / INRAP / Ministère de la culture et de la communication). 3. Dark sandstone with a clay matrix. 4. Sintered material generally colored blue or green. Biology Mending Brittle Bones BY EMMA WALTON Micro-X-ray tomography of mouse metatarsals treated with Dock5 inhibitor C21 (left), and untreated (right). © G. CRES/CNRS/CRBM With population ageing, the prevalence of osteoporosis, a progressive bone disease, is on the rise. Yet current treatments are far from satisfactory. Now, CRBM1 researchers led by Anne Blangy have come up with a novel therapeutic strategy that shows great promise in animal models.2 Our skeleton is remodeled throughout life. Cells called osteoclasts remove or “resorb” old bone, while osteoblasts deposit newlyformed bone. These processes are normally balanced but in osteoporosis, the scales tip in favor of osteoclasts, leading to loss of bone density and susceptibility to fractures. Postmenopausal women are most at risk because low estrogen levels increase osteoclast activity. Most treatments for osteoporosis eliminate osteoclasts. Yet these cells also secrete proteins that stimulate osteoblast growth, so wiping them out completely impairs bone formation. Blangy’s team put forward a new strategy to tackle these rogue cells. During resorption, osteoclasts form a tight seal on bone, “much like a plunger over a blocked drain,” explains Blangy. They then secrete acid and proteases, which break down bone. “If we can prevent the formation of this seal, then we may block bone resorption while preserving the other functions of osteoclasts,” she adds. After years of research, Blangy’s team identified an essential component of the osteoclast seal called Dock5. Finally, the researchers could test their theory in an animal model. Like humans, mice with low estrogen levels are prone to osteoporosis and those that have had their ovaries removed develop the condition within weeks. Blangy treated these mice with an inhibitor of Dock5 called C21 before measuring bone density and markers of bone turnover. Remarkably, treatment with C21 provided effective protection against bone loss without limiting the formation of new bone. Blangy hopes that investment from the pharmaceutical industry will help make C21 or C21-based molecules readily available in health institutions and allow patients with osteoporosis to put a spring back in their step. ii 1. Centre de recherche de biochimie macromoléculaire (CNRS / Université de Montpellier). 2. V. Vives et al., “Pharmacological inhibition of Dock5 prevents osteolysis by affecting osteoclast podosome organization while preserving bone formation,” Nature Communications, 2015. 3(6): 6218. anne.blangy@crbm.cnrs.fr A patch of the southern sky based on observations performed by ESA’s Planck satellite at microwave and sub-millimeter wavelengths. Astrophysics The Early Universe in Focus The European Space Agency’s (ESA) Planck satellite has stopped collecting data since August 2013, yet full analysis of these observations will keep astrophysicists busy for at least a decade. Two years ago, researchers from the Planck collaboration thus published the most precise map ever of the temperature fluctuations in the cosmic microwave background radiation (CMB)—the oldest light in the Universe, emitted some 380,000 years after the Big Bang. They are now studying the polarization of this fossil radiation, caused by the interaction of light with the matter it went through. The researchers are thus able to retrace the tumultuous history of our Universe from its infancy to the present day. © ESA/PLANCK COLLABORATION Oncology Biopsy-free Skin Cancer Diagnosis BY FUI LEE LUK http://www.damaemedical.fr arnaud.dubois@institutoptique.fr In September 2014, an inspired optical imaging specialist teamed up with two entrepreneurial-minded engineering graduates. Their collaboration led to the creation of DAMAE Medical, a CNRS start-up company currently developing a cutting-edge method for detecting skin cancer. Based on optical coherence tomography (OCT), which uses light waves to produce crosssectional images of skin tissue, the innovation is remarkably fast, effective, and non-invasive when compared with the conventional biopsy-based approach. Today, most skin disorders are diagnosed by removing skin samples for laboratory analysis: a procedure that can leave scarring—unnecessarily so when moles prove benign—and takes time for results to come back. The technology devised by DAMAE Medical co-founder and chief scientific officer Arnaud Dubois of the LCF1 could overcome these drawbacks. Patented in 2013, it uses an improved OCT technique to obtain high-resolution images of skin structure in real time. The new method not only provides similar resolution to histology images visible by traditional microscopic analysis of excised tissue samples, but it also gives feedback up to 1 mm deep— penetrating deeper than other high-resolution optical imaging methods. Moreover, as the process leaves the tumor intact, further testing is possible if necessary. By this summer, the team will have completed three prototypes—the first of which is already “operational and efficient,” notes Dubois. The last one will be clinically tested at Hôpital Saint-Louis in Paris later this year prior to commercialization, scheduled for 2016. The team is now “working to create a portable, user-friendly system via software development and miniaturization.” DAMAE Medical won the French government’s 2014 Worldwide Innovation Challenge and the Altran Foundation’s 2014 International Award. Dubois foresees “sales in Europe and the US, as well as in all countries with a high incidence of skin cancer, such as Australia.” ii www.damaemedical.fr arnaud.dubois@institutoptique.fr 1. Laboratoire Charles Fabry (CNRS / Institut d’Optique Graduate School / Université Paris-Sud). Information Technology A Vote of Confidence for the LORIA BY FUI LEE LUK Voting has come a long way since Ancient Greeks pioneered democratic elections. Today, electronic polling makes it possible, at the touch of a button, to cast or count millions of votes at a time. Yet this technology also poses new security hazards. Scientists at the LORIA1 are actively fighting these risks via cryptographic algorithms and protocols to meet what CNRS senior researcher Véronique Cortier calls “a paradoxical dual need for voter privacy and result transparency.” From public or private elections to voting contests, e-voting offers significant advantages over paper ballots, such as automated vote tallying, reduced costs, and wider access for online voters. E-ballots, however, face new threats like computer viruses, hacking, power cuts, and server shutdowns. Remote Internet voting also increases the risk of fraud, where an individual illicitly votes for another. The LORIA’s answer to these threats is called Belenios. Launched in 2014, this secure web-based ballot box system combines the two vital components of effective security solutions. The first is privacy, as the voter’s computer encrypts the ballot to keep it secret. The second is transparency, enabling all voters to check that their ballots are in, and that each valid one is counted in the tally. Belenios builds on Helios, created by Harvard’s Ben Adida in 2009, and enhances it by preventing ballot stuffing, i.e., the unauthorized casting of more than one vote. Having successfully tested Belenios, the LORIA is now working to make it available to the general public. In December 2014, the laboratory also signed an agreement with Spanish firm Scytl, whose leading e-solutions covering election cycles from pre- to post-election are already used in Europe, Africa, the Americas, and Asia- Pacific. This collaboration should “further increase the potential of e-voting and improve existing solutions,” notes Cortier. By partnering with a company present in 38 countries, the lab is now set to extend its influence to ballot boxes across the world. ii © SCYTL SECURE ELECTRONIC VOTING More than 280,000 votes were cast online in the 2015 state elections in New South Wales (Australia) using Scytl technology. 1. Laboratoire lorrain de recherche en informatique et ses applications (CNRS / INRIA / Université de Lorraine). veronique.cortier@loria.fr IN DEPTH Studies on this African grass rat help elucidate biological rhythm disorders in humans. FEATURE SPECIAL REPORT PROFILE PROFILE PORTFOLIO PORTFOLIO SPECIAL REPORT Animal Testing under Scrutiny BY SAMAN MUSACCHIO Research. As animal activist action gains momentum in Europe, CNRS International Magazine surveys worldwide regulations that cover this much-debated and little-known aspect of research. 18 CNRS INTERNATIONAL MAGAZINE Nobody wants to do this research, let me be very clear,” insists Roger Lemon, a leading British neuroscientist 1 who studies hand and finger control in humans and non-human primate models. “Like most people, I would like to see the day when animal research is no longer necessary. But for anybody who understands the complexity of the killer diseases in our society, including cancer, neurodegenerative disorders like Alzheimer’s and Parkinson’s, as well as global threats like Ebola, it’s very difficult to replicate the biology in silico or in vitro.” Lemon is not new to the debate setting animal rights groups against the scientific community. Ten years ago, the UK was the hotbed of violent protests and intimidation tactics targeting all those involved in animal research, from the construction workers that built the facilities to the lab technicians that operated them. Today, these headline-grabbing actions have spread to other European countries. In Italy in 2013, activists broke into the animal facility of the University of Milan, mixing up cage labels and freeing some 1600 animals used for studying autism and schizophrenia, rendering years of research obsolete. In Germany last September, staff at the Max Planck Institute for Biological Cybernetics in Tübingen were threatened following the television broadcast of a video showing monkeys undergoing experiments, and politicians were asked to shut down the research program. In France, insults and attacks on social networks have targeted researchers from the neuroscience institute at la Timone (INT)2 in Marseille, which houses mice and non-human primates (NHPs) used in neurological and psychiatric research. In addition to all this, the research community is very concerned about the intense lobbying by animal rights groups to reform current EU legislation regulating biomedical research involving animals. On March 4, Stop- Vivisection,3 a European Citizen’s Initiative (ECI)4 which attracted more than 1.2 million votes in 26 of the EU’s 28 member states, was submitted to the European Commission. The supporters of this ECI, whose objective is to prohibit all animal research in Europe, will now make their case in a public hearing held by the European Parliament, giving the Commission three months to respond. A history of debate “And yet there is not a single medical advance that has not required the use of animals in some way,” exclaims François Lachapelle, who heads the national animal welfare office of INSERM.5 And examples abound. In 1881, Louis Pasteur proved germ theory by inducing anthrax in sheep. Frederick Banting, Charles Best, and John Macleod first isolated insulin from dogs in 1922, paving the way for today’s diabetes treatments. Jonas Salk used rhesus monkeys to isolate the polio virus, leading to a vaccine by 1955. In fact, “of the 105 Nobel Prizes in Physiology or Medicine, 91 were dependent on animal research,” adds Lachapelle. Yet with increased understanding of animal biology came the realization that these sentient beings experience pain and distress, raising ethical questions as to whether the benefits to humans justified the harm done to animals (see box p. 21). Mass appeal Numbers are compelling. In 2011 alone—the most recent data available—nearly 12 million vertebrates were used for experimental and other scientific purposes across the EU.6 Worldwide estimates range from 75 to 100 million specimens a year, with China accounting for 35 million, but there are no official statistics. The US, for example, reported FEATURE © H. RAGUET/CNRS PHOTOTHÈQUE … In Paris on April 26, 2014, a demonstration was held, calling for the ban of scientific research on animals. © CITIZENSIDE/B. MÉNIGAULT/AFP 1. Institute of Neurology, University College London (UK). 2. Institut de Neurosciences de la Timone (CNRS / Aix-Marseille Université). 3. www.stopvivisection.eu 4. To be accepted, an ECI must obtain more than one million signatures in more than seven member states within three months. This is the fourth ECI to be approved since the Treaty of Lisbon (ratified in 2007). 5. Institut National de la Santé et de la Recherche Médicale. 6. Source: Seventh Report from the Commission to the Council and the European Parliament on the Statistics on the number of animals used for experimental and other scientific purposes in the member states of the European Union. 19 SPRING 2015 N° 37 20 using just under one million animals a year7—excluding the most prevalent research species: mice, rats, birds, and fish. In Europe, rodents account for 80% of the total number of vertebrates used in laboratories (see chart for breakdown ). Invertebrates are not subject to statistics, although they are common in research—the best known being the fruit fly (Drosophila melanogaster) and C. elegans nematode— and are generally unprotected by the law, with some notable exceptions. “However high these numbers may seem, they are very small compared with the animals destined for human consumption as food,” explains Ivan Balansard, a veterinarian from the animal welfare office of the CNRS. A recent study shows that in Europe, for every single research animal, 200-300 are slaughtered for human consumption. For each non-human primate in research, 500,000 animals are bred for food.8 How exactly are these animals used? The vast majority of procedures apply to biomedical research, which includes anything from basic research to the development of drugs, behavioral studies, xenotransplantation, testing and safety (see chart for breakdown). “French legislation, for example, requires that a drug candidate be tested on a rodent and non-rodent model before it can make it to phase I human clinical trials,” says Balansard, who notes that a lot of the research also helps develop treatments for animal pathologies. “And of course, there is strict control over all these procedures,” he points out. A new Directive European legislation on animal testing is embodied by Directive 2010/63/EU, which ensures that the 3Rs principle (see box p.21) is applied at every stage of the research process. Each application to carry out animal research now involves a cost/benefit assessment that sets the scientific benefit against the potential harm done to animals. A particular species can only be used when no “lower” animal model is suitable for a specific research, and invasive procedures on great apes such as chimpanzees are prohibited. New standards on caging and housing have also been established. “Changes are significant and the new regulations put considerable strain on biomedical research. But since they improve animal welfare, the research community has been keen to accept them,” says Balansard. “This is what makes the ECI’s stance regarding this legislation so surprising—we are approaching a level of animal welfare that is unparalleled in the world, and in any other field.” Applications and beyond The Directive, which came into force on January 1, 2013, has already been adopted in most EU countries. France, which passed the first legislation on animal testing in 1987, has fully complied with it. Today, every project is first evaluated by an ethics committee—which includes veterinarians, researchers, technicians and members of the public—before being granted final authorization by the Ministry of Research. In Germany, “EU legislation brought few large-scale changes, given the high level of regulation in place before the introduction of the new Directive,” explains Stefan Treue, a cognitive neuroscientist who operates the country’s largest primate center in Göttingen.9 Regional government offices still have the last say in approving or denying a research project—which leaves room for local interpretation. One change is that each research institution must now have its own Institutional Animal Care and Use Committee (IACUC)—a board that checks applications before they are sent to the local authorities for approval. “Legislatively, it’s a rather calm situation.” As for the UK, “there are a few instances where the Directive is slightly different from our pre-existing national regulations—for example, as regards cage sizes,” says Lemon. The UK has also decided to keep a personal license system in place for anyone who does animal testing, which Percentages of animals used by classes in EU member states Mice 60.96% Rats 13.96% Guinea-pigs 1.49% Other mammals 0.07% … Other rodents 0.47% Prosimians+monkeys +apes 0.05% Rabbits 3.12% Carnivores 0.25 % Artio+Perissodactyla 1.28% Cold-blooded animals 12.47% Birds 5.88% Purposes of experiments Research and develop human +veterin+dentist 18.8% Biological studies of a fundamental nature 46.1% Production and quality control of products for human medicine and dentistry 10.97% © C. HEIN FOR CNRS MAGAZINE Production and quality control of products for veterinary medicine 2.94% Toxicological and other safety evaluation 8.75% Other 9.27% Education and training 1.56% Diagnosis of disease 1.61% Source: Seventh Report from the Commission to the Council and the European Parliament on the Statistics on the number of animals used for experimental and other scientific purposes in the member states of the European Union. 7. Source: USDA, Annual Report Animal Usage, 2011. 8. R. Roelfsema and S. Treue, “Basic Neuroscience Research with Nonhuman Primates: A Small but Indispensable Component of Biomedical Research,” Neuron, 2014. 82(6): 1200-04. 9. Cognitive Neuroscience Laboratory (CNL) at the German Primate Center (DPZ) in Göttingen (Germany). 10. Peter Singer is best known for his seminal book, Animal Liberation: a New Ethics for Our Treatment of Animals (New York: New York Review, 1975). 11. W.M.S. Russell and R.L. Burch, The Principles of Humane Experimental Technique (London: Methuen, 1959). 21 is not required by the EU Directive. “The situation, however, is not easy as regulations controlling research have been under close reexamination since 2010, and the anti-vivisection lobbies see this as a perfect opportunity to step up their efforts against biomedical research. Sadly, high-impact actions by extremists have now spread to countries like Italy.” Italy “The situation here is extremely disconcerting,” confirms Silvio Garattini, director of the Milan-based Mario Negri Institute for Pharmacological Research, where some 750 people are involved in basic and clinical research on cancer, psychotropic drugs, or organ transplantation, which includes animal testing, mostly on mice and rats. The reason for his pessimism is that the Italian Parliament restricted the already tight regulations governing animal research by drafting legislation that goes above and beyond the framework of the EU Directive. “This is contrary to Article 2 of the Directive and the Commission has already warned the Italian government,” says Garattini. The Parliament has outlawed the breeding of cats, dogs, and monkeys for research purposes, put a moratorium on addiction-related studies, and forbidden the use of animals for xenotransplantation. “We cannot transplant human tumors in mice that are immunologically incompetent, for example. Yet this is essential for our research, since it allows us to study the behavior of tumors in a living organism.” Although © CNRS The new EU Directive applies strict rules on caging and housing of animals, such as NHPs (pictured here). Rise of the 3Rs Contemporary philosophers like Peter Singer,10 who continue to advocate more ethical treatment of animals, trace the first seeds of this great shift in paradigm to eighteenth century England and the founder of modern utilitarianism, Jeremy Bentham. No longer should animals be viewed as property, with no mind or reason: the ability to suffer should be the benchmark of how we treat other beings. Perhaps fitting that the UK would become the first country in the world to enact laws to protect animals—first cattle from improper treatment in 1822, and soon after, the first-ever piece of legislation on animal experimentation: the Cruelty to Animals Act of 1876. It ensured that “the proposed experiments are absolutely necessary for the due instruction of the persons to save or prolong human life.” Less than a century later, the 1959 seminal book The Principles of Humane Experimental Technique,11 would describe key guidelines that continue to structure animal testing legislation to this day, and across the world, hereafter referred to as the 3Rs: 1. REPLACE the use of animals with alternative techniques, or avoid the use of animals altogether. 2. REDUCE the number of animals used to a minimum, to obtain information from fewer animals or more information from the same number of animals. 3. REFINE the way experiments are carried out, to make sure animals suffer as little as possible. This includes better housing and improvements to procedures that minimize pain and suffering and/or improve animal welfare. Although most countries in Europe operated under these ethical guidelines, few of them (notable exceptions being the UK and Germany) had any enforceable legislation on animal testing until the first EU Directive in 1986 (86/609/EEC). … Italian researchers have secured a moratorium until the end of 2016, “new regulations are causing long delays in obtaining government authorizations when animal testing is involved. This in turn hinders our international collaborations. It also means we must abandon certain types of research,” adds Garattini. “I see this as a warning to scientists that they will soon have to give up animal testing altogether.” US prospects “Any ban on animal research would pose a serious problem for Europeans, especially when it comes to basic and translational biomedical research,” says Alexander Ploss, a prominent virologist member of the Princeton University (US) IACUC. In the US, all programs involving animal research must first be evaluated by an IACUC, which is set up by the research organization. “Many institutions also try to get accreditation from the AAALAC,12 an independent body whose role is to ensure that regulations are enforced. It is not mandatory, but it helps when it comes to publications and obtaining federal funding,” he adds. “In terms of animal protection, the US was more advanced than countries like France in the 1960s—its Animal Welfare Act dates back to 1966,” says Balansard. “But requirements concerning animal caging, for example, are more stringent in Europe,” he points out. Another significant difference is that the US still allows research on great apes, although the NIH (National Institutes of Health) no longer funds studies on chimpanzees. “This has hindered progress on hepatitis, as there is no other suitable species,” says Ploss. “Public authorities and the NIH are aware that much of this research cannot be done without these animal models, let alone without testing on vertebrates like rats or mice. There is no indication that legislation regarding NHPs will change,” he concludes. Heading East “One of the risks of pushing for harsher legislation is delocalizing research,” says Lachapelle. The destination of choice is China, which already sources the majority of primates for research in Europe and the US. Some centers hold as many as 50,000 animals. “The Chinese are ready for this. And they’re not competing by being cheap. Their facilities are becoming very good, they have started applying international standards and have advertised a lot in the US and Europe,” adds Treue. For international pharmaceutical companies, the country’s legislative stability makes it particularly attractive. Yet “academic research is different,” he points out. “I’m not going to close my lab and move to China. But the outsourcing of certain aspects and individual procedures will increase.” Erwan Bézard, a neuroscientist who runs a Bordeauxbased facility dedicated to Parkinson’s disease,13 was one of the first to outsource part of his research to China. Opened in 1999, his 1500 m2 facility in Beijing now houses 150 rhesus macaques. “One of the problems with research on primates is small sample size, which can limit the statistical reach of certain results,” says Bézard. “I use NHPs in numbers that need to be statistically valid, so China was the logical destination to achieve these numbers. In terms of legislation, it was very rudimentary at the time, but today, the Chinese abide by exactly the same rules as the US in terms of housing standards and animal welfare. My facility has obtained the AAALAC certification and we also apply the 2010 Directive … © PHOTOS: CNRS 12. www.aaalac.org 13. Institut des maladies neurodégénératives (CNRS / Université Victor Segalen-Bordeaux-II). 14. P. Tabakow et al., “Functional regeneration of supraspinal connections in a patient with transected spinal cord following transplantation of bulbar olfactory ensheathing cells with peripheral nerve bridging,” Cell Transplantation, 2014. 23(12):1631-55. 15. www.basel-declaration.org 16. Groupe interprofessionnel de réflexion et de communication sur la recherche (www.recherche-animale.org). 17. The European Animal Research Association (EARA) http://eara.eu/home; http://www. understandinganimalresearch.org.uk; Fédération européenne des neurosciences (http://www.fens.org). Ongoing cognitive research on NHPs. To get its reward, the rhesus macaque must make specific gestures following visual stimulation. A researcher measures its cerebral activity during each experiment. since we receive funding from the EU.” China is a real competitor, and hopes to dominate the market within 20 or 30 years if Europe decides to ban research on NHPs. Alternatives Why not do away with animal models altogether? The first “R” in the “3Rs”—”replace”—has been interpreted by animal rights groups as replacing live animals entirely by in vitro or in silico alternatives (computer models). “This ‘alternative tests’ business is completely non-existent,” exclaims Garattini. “Cells cultivated in vitro are not living organisms. If you are investigating whether a drug alleviates pain, or has an effective cognitive function, it is no help to look at the cells or ask a computer. True enough, 70% of research at our center is done in vitro, but these are complimentary studies, not alternatives.” As for computer models, “they are great, but they are often based on data obtained from animal experiments,” adds Lemon. “For example, after someone suffers a paralyzing spinal cord injury, complex changes occur at the cellular and molecular level. These are difficult to replicate in a non-animal model system, particularly with regard to the actual wiring of the nervous pathways in the spinal cord. The most promising treatments have required years of research14 involving many animals,” he says. Another argument put forth by anti-vivisectionists is that some animal models are too different from humans to be of use. “There is not a single animal that is good for everything,” adds Garattini. “For instance, we have performed studies on drugs that act on lipids—for treating cholesterol. Mice are not very useful, rats are somehow sensitive, but rabbits display a very important parallel with humans for that kind of research. For Ebola, it is important to select certain types of monkeys, for others, it is dogs and so on,” he adds. “We are doing research. We are at the frontier of knowledge, so many times, we get it wrong. But if you look at history, we have been able to cure many ailments in humans by experimenting on animals. Furthermore, the fact that there is some kind of transferability means that many drugs that have been developed for humans are also used to treat animals.” A proactive approach “There has been insufficient public debate on why this research is necessary, and the Italian situation is a warning to us all,” insists Lemon. He is not alone. The research community now encourages greater communication on the subject. “We have had a long tradition of discretion about our research. This is disastrous In the long run, since it creates the impression that animal testing does not exist,” explains Treue, who was an important architect of the 2010 Basel Declaration, a public appeal for animal research signed by 3500 scientists.15 In France, Lachapelle presides the GIRCOR,16 a think-tank that provides information about animal research to the government and general public and includes 40 research institutions and universities. This communication model is now ubiquitous in many countries and throughout Europe.17 “In my opinion, biomedical research is on the brink of extremely exciting developments,” says Lemon. “Unfortunately, the pressing demands of complex degenerative diseases in humans will probably mean an increase in the use of animal models, but this should not be considered as a problem as long as we continue to uphold the 3Rs,” he concludes. He thus echoes the voice of another concerned scientist, who in 1875 wrote to the president of the Royal Society—then also under attack from antivivisectionist groups: “The object is to protect animals, and at the same time not to injure physiology.” His name was Charles Darwin. ii “Many drugs that have been developed for humans are also used to treat animals.” CNRS INTERNATIONAL MAGAZINE WORLDWIDE PARTNERSHIP NEWSWIRE 38 Going Small, Thinking Big © A. BACCOUCHE, A. GENOT, T. FUJII, Y. RONDELEZ Nanosystems. A French-Japanese laboratory celebrates 20 years of excellence and looks to the future. BY ARBY GHARIBIAN I n January, the oldest and largest CNRS International Joint Unit (UMI) in Asia, LIMMS,1 celebrated two decades of collaboration with Tokyo University for the development of nanosystems. CNRS officials and the ambassador of France in Japan attended the event, alongside the General Director of the IIS,2 the laboratory’s host institution. A room was dedicated to the memory of Jean-Jacques Gagnepain, who, as scientific director of the former CNRS Department of Engineering Sciences (PSI), initiated the creation of the laboratory back in 1994, together with Fumio Harashima, then director of the IIS. “The inception of the LIMMS was rooted in two forward-looking ideas,” explains Dominique Collard, co-director of the laboratory. “One was that microsystems would have increasingly broad applications, and the other was that international cooperation between scientists with different approaches would spur scientific achievement. In this case, Japanese emphasis on technology and prototype development was matched with French expertise on theoretical conception and simulation.” A recipe for success The laboratory has a strong track record, boasting more than 60 faculty and staff, 150 visiting scientists over the course of its existence, and a plethora of peer-reviewed publications and patents, in fields as varied as bioengineering and micro-optics. “Working together over time has helped build a climate of trust fostering performance,” continues Collard. “The Japan Society for the Promotion of Science (JSPS) provided, and continues to provide, key financial support, and the complementary nature of French and Japanese scientific skills enabled us to achieve results that would not have been possible individually.” Cutting-edge Japanese capabilities in microtechnology and precision engineering, combined with French know-how in optics, electromagnetics, or biology, helped expand the scope and impact of new technologies. Beyond the frontiers of research The laboratory focuses on three areas: Advanced-MEMS, Bio-MEMS, and nanotechnology. The first two aim to develop microelectromechanical systems (MEMS), respectively for sensors and actuators used in intelligent systems, and for biological organisms. In the field of Advanced-MEMS, researchers have fashioned composite materials, one of which consists of both crystals—for their good mirror quality—and polymers, which are highly flexible. This made it possible to develop wide-angle reflection systems for use in scanners. The scientists have also designed intelligent surfaces— equipped with microcilia actuators to transport objects, and optical sensors to detect their location and shape—that have many potential industrial uses, including for sorting systems in recycling plants. Another significant achievement in this field was the development of silicon nanotweezers, which can characterize DNA bundles simply by gripping them. This mechanical method for cell analysis has proven to be an invaluable complement to the marking techniques currently used in genetic research. In the area of Bio-MEMS, laboratory teams developed a nanotransportation system mimicking those operating inside cells. A filament known as a microtubule acts as a kind of “rail,” which the motor protein kinesin can ride, moving cargo such as molecules through very small channels. Using the silicon nanotweezers also developed by the laboratory, researchers can lay these rails in “tracks” serving Water-in-oil emulsions used to investigate the dynamics of complex molecular programs. 1. Laboratory for Integrated Micro Mechatronic Systems (CNRS / Institute of Industrial Science of the University of Tokyo). 2. Institute of Industrial Science of the University of Tokyo. 3. Yannick Rondelez was awarded the 2014 CNRS Bronze Medal for his research summarized in “Predator–Prey Molecular Ecosystems,” ACS Nano, 2013. 7 (1): 27–34.) 4. FP7 INCOLAB: Europe-Japan Opening of LIMMS. 5. Seeding Microsystems in Medicine in Lille – European- Japanese Technologies against Cancer. 39 specific medical or research purposes, such as for tissue engineering. In another project, which won the CNRS Bronze Medal,3 researchers used synthetic DNA strands to develop a molecular computation system able to simulate the complex mechanisms at play in predator-prey ecosystems, such as population oscillation. This exciting development in DNA computation could become a useful tool for molecular biologists, for example in the development of self-delivering smart drugs. The final area of focus is nanotechnology, which researchers use to enhance existing scientific systems. For instance, they equipped a transmission electron microscope with a microactuator that can move a nano-object and then observe it with atomic resolution, thus providing a better understanding of how matter behaves on the atomic scale. This in turn makes it possible to design materials that are more robust, or that can conduct heat more efficiently. Yet such nanostructures require expensive equipment to produce. Researchers have therefore developed alternative techniques using existing instruments rather than specialized devices, in an effort to create nanowires at low cost. A European future The past two decades have seen dramatic changes in the scientific landscape— and within the LIMMS. In 2011, it was selected by the European Commission as one of its six international laboratories, and renamed EUJO-LIMMS.4 French and Japanese researchers now work in a truly international setting, alongside colleagues from Switzerland, Germany, Finland, and the Netherlands. “The French-Japanese relationship goes on within this larger European context,” concludes Collard. “In 2014, the SMMIL-E5 project created a mirror site at the Centre Oscar Lambret university hospital in Lille, to apply the laboratory’s innovations in a clinical environment.” And the University of Tokyo sees the laboratory as one of its most important international initiatives. In addition to technology transfer and the creation of start-up companies, the LIMMS has obtained encouraging results, such as the development of pads that heal wounds faster, and the successful use of nanotweezers to expose DNA to irradiation for cancer treatment evaluation. “Those are only the most recent achievements in our long-standing collaboration, which we look forward to pursuing.”ii collard@iis.u-tokyo.ac.jp © LIMMS/CNRS-IIS The researchers of the LIMMS are actuating a microsystem inside a transmission electron microscope. Monitoring of a DNA bioreaction with silicon nanotweezers. © L. JALABERT CLOSE-UP A Good Pitch Brass instruments can be quite loud, and trombones are no exception. Musicians use various devices to dampen the emitted sound, the most common being the straight mute—like the one pictured below the table. Yet once muted, lower notes—known as pedal tones—become distorted, and the lowest two for this trombone are impossible to play. In this anechoic chamber, Thibaut Meurisse from the STMS,1 is measuring the acoustic impedance of a trombone to adjust the “active” mute settings to make these notes playable. “Much like noise-cancelling headphones, we have developed a prototype ‘active’ mute with a microphone to capture the sound field within the instrument, and a speaker producing a command signal that can control, and possibly suppress any distortion,” he explains. The researchers hope to eventually enclose all the electronic components inside the mute, making it a stand-alone equipment that would not only dampen the sound, but also allow the musician to create entirely new sounds. adrien.mamou-mani@ircam.fr A photo gallery is available online: www.cnrs.fr/cnrsmagazine 1. Sciences et technologies de la musique et du son (IRCAM / CNRS / Université Pierre et Marie Curie / Ministère de la culture et de la communication). PHOTO: C. FRÉSILLON/IRCAM/CNRS PHOTOTÈQUE 43 SPRING 2015 N° 37