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BIF fellows present 15 new PhD projects and 6 completed theses
FUTURA THE JOURNAL OF THE BOEHRINGER INGELHEIM FONDS Schusterstr. 46-48 55116 Mainz Germany Tel. +49 6131 27508-0 Fax +49 6131 27508-11 E-mail: [email protected] www.bifonds.de 01 Titel_RZ.indd 8 The Rhythms of Life How do our inner biological clocks keep track of time? Projects and Results BIF fellows present 15 new PhD projects and 6 completed theses. VOL. 28 | 1.2013 Ernst Jung Prize for Ivan Dikic BIF research award holder receives the prize for his work on ubiquitin. 19.06.13 10:46 CONTENTS FUTURA 28 | 1.2013 FUTURA THE JOURNAL OF THE BOEHRINGER INGELHEIM FONDS PUBLISHING INFORMATION VOL. 28 | 1.2013 Published by Boehringer Ingelheim Fonds Schusterstr. 46-48 55116 Mainz Germany Tel. +49 6131 27508-0 Fax +49 6131 27508-11 E-mail: [email protected] www.bifonds.de The Rhythms of Life How do our inner biological clocks keep track of time? Projects and Results BIF fellows present 15 new PhD projects and 6 completed theses. The cover illustration shows a simplified model of the Golgi ap- Stiftung für medizinische Grundlagen- paratus and some lysosomes. The latter are responsible for the forschung degradation of macromolecules and contain more than 60 hydro- Schusterstr. 46–48 lases, among them sphingolipidase-b-gluco-cerebrosidase (GBA). 55116 Mainz In her thesis, BIF fellow Friederike Zunke examines how GBA is Germany transported into the lysosome. See page 28 for more details. Tel. +49 6131 27508-0 Ernst Jung Prize for Ivan Dikic BIF research award holder receives the prize for his work on ubiquitin. Fax +49 6131 27508-11 25.02.13 09:34 E-mail: [email protected] www.bifonds.de Editor-in-Chief Dr Claudia Walther Editors Dr Kerstin Terrenoire (BIF, executive FACTS editor), Dr Anja Hoffmann (BIF, executive editor), Kirsten Achenbach (BIF executive 4 Science News corporate communications gmbh) THE RHYTHMS OF LIFE How do biological clocks in organisms keep track of time? editor), Karsten Fiehe (muehlhausmoers 8 Authors in this issue Michael Simm, Dr Kerstin Terrenoire, Carolin von Schoultz, Dr Claudia Walther FELLOWS PROJECTS Translating, copy-editing and proofreading Adam In the interest of our fellows, we do not publish this section online. Blauhut, Dr Caroline Hadley, Dr Caroline M. In November 2012, the Board of Trustees of the Boehringer Ingelheim Fonds discussed Taylor, Dr Susan Simpson, Shirley Würth 42 applications selected from the 216 submissions to the secretariat. In the end, 17 applications were approved and so far 15 fellowships have been taken up. 13 communications gmbh, RESULTS www.muehlhausmoers.com Six former fellowship holders give brief accounts of their results and their scientific publications. Production muehlhausmoers corporate Project management Karsten Fiehe 29 Art direction Britta Siebert Printed by Sommer Druck, Dieselstr. 4, F O U N DAT I O N Profiles 91555 Feuchtwangen, Germany 33, 34 New Trustees for BIF 37 Upcoming events 37 left); Gabrielle DeMarco (bottom right) 33 Publication date of current issue July 2013 WHO’S WHO AT BIF Prof. U. Benjamin Kaupp answers the BIF questionnaire. 34 PERSPECTIVES From scientist to consultant: interview with Dr Oliver Müller. 35 A BIF FELLOW’S GUIDE TO ... ZURICH Discover the beauty of Switzerland’s largest city. stated otherwise Cover photos avenueimages/Thomas Frey (bottom THIRTY YEARS AGO: BIF’S BEGINNINGS Since 1983 BIF has celebrated many successes, grown and seen many changes. Images Boehringer Ingelheim Fonds, unless 36 BIF FUTURA is the journal of the Boehringer Ingelheim Fonds, a non-profit organization supporting basic research in biomedicine. Opinions expressed in BIF FUTURA cannot automatically be assumed to be the official standpoint of the Boehringer Ingelheim Fonds. This is particularly the case when the article is accompanied by the name of the author. Reproduction of articles or parts of the journal only with reference to and the permission of the foundation. 2 02-03_Inhalt.Edi_RZ.indd 2 19.06.13 10:23 EDITORIAL BOEHRINGER INGELHEIM FONDS FUTURA 28 | 1.2013 STAYING POWER It took him nearly 25 years to unravel the anatomy of the haemoglobin molecule, the oxygen transporter in our blood. And yet, when he was awarded the Nobel prize for his work, Max F. Perutz remarked “… the task which I have set myself has only just begun.” Such are typical journeys of discovery in basic research. Limits – or even laws – need to be overcome. New, groundbreaking methods may have to be developed, new schools of thinking may need to flourish – sometimes in seemingly remote, exotic fields – to eventually arrive at a “Eureka!” moment. What company would or could allow their researchers to pursue projects that have no obvious purpose for decades? How many changes in ownership or management could such projects survive? How wide could their range of topics be? »Basic research requires the dedication and enthusiasm of our most talented people.« A further example of the timescales involved: Abbe’s law. Formulated in 1873 by physicist, mathematician and astronomer Ernst Abbe, it postulated a physical limit to the resolution of light microscopy. With Abbe’s work on optical theory at the University in Jena revolutionizing microscopy (and making him rich), his law was regarded as being insurmountable for more than 100 years. However, in 1994, Stefan Hell, a Heidelbergtrained physicist, had the decisive idea of how to break this limit. By achieving superresolution, he literally opened new dimensions in light microscopy as well as in cell biology, and further fields may follow. Currently, basic academic research in Germany finds itself in a comparatively privileged situation with regard to financial support. Other countries, such as the USA and the Netherlands, are shifting their emphasis from basic to translational research with profound consequences. It seems time (again) to stress the importance of basic research and discuss the roles of public and private funding. Basic research promises no short to medium term return of investment. And while the list of examples highlighting the crucial role of its ground work ranges from satellite navigation systems to vaccines against particular forms of cancer, basic research is a very unpredictable fellow. Or as Perutz once put it: “Discoveries cannot be planned, they pop up, like Puck, in unexpected corners.” Moreover, the often complicated or seemingly exotic topics usually generate no flashy news, nor limelight – as we well know at BIF. Academic researchers also seldom make a fortune. And yet, basic research requires the dedication and enthusiasm of our most talented people, as well as stamina, a long-term perspective and courage from funding organizations. After all, most of the purely curiosity-driven endeavours will never lead to any useful product or therapy at all. However, they may well provide insights that change our understanding of the world. Dr Claudia Walther, Managing Director 3 02-03_Inhalt.Edi_RZ.indd 3 19.06.13 10:23 FACTS FUTURA 28 | 1.2013 Antiviral Antiviral Antiviral BOEHRINGER INGELHEIM FONDS Inflammatory Inflammatory Inflammatory Antiviral Antiviral Ankrd17 Ankrd17 Nek6 Nek6 Met Met Ptprj Ptprj Jun Jun Arhgap21 Arhgap21 Crkl Crkl Mapk9 Mapk9 Map3k7 Map3k7 Tbk1 Tbk1 Tnfaip2 Tnfaip2 Zc3h14 Zc3h14 Sqstm1 Sqstm1 Plk2/4 Plk2/4 Irf4 Irf4 Syk Syk Irf8 Irf8 Samsn1 Samsn1 Dock8 Dock8 Sash1 Sash1 Stat4 Stat4 Stat1 Stat1 Nfatc2 Nfatc2 Inflammatory Etv6 Etv6 Mapkapk2 InflammatoryMapkapk2 Irf9 Irf9 Stat2 Stat2 Atf3 Atf3 Rbl1 Rbl1 Mark2 Mark2 Tank Tank Myd88 Myd88 Nfkbiz Nfkbiz Cebpb Cebpb Nek7 Nek7 Rgs1 Rgs1 Phlpp Phlpp Ppm1b Ppm1b Ikbke Ikbke Rgs2 Rgs2 Atf4 Atf4 Mertk Mertk Map3k8 Map3k8 Ptpre Ptpre Hat1 Hat1 Socs6 Socs6 Plagl2 Plagl2 Dusp14 Dusp14 Ptpn1 Ptpn1 Runx1 Runx1 Rela Rela Pnrc2 Pnrc2 Hmgn3 Hmgn3 Plk2 Plk2 -1 Correlation -1 Correlation 1 1 Candidate Candidate Canonical Canonical Inflammatory (TF) Inflammatory (TF) Antiviral (TF) Antiviral (TF) DEFENCE PATHWAYS Ankrd17 Nek6 Met Ptprj Jun Arhgap21 Crkl Mapk9 Map3k7 Tbk1 Tnfaip2 Zc3h14 Sqstm1 Plk2/4 Irf4 Syk Irf8 Samsn1 Dock8 Sash1 Ankrd17 Stat4 Nek6 Ankrd17 Met Stat1 Nek6 Ptprj Met Nfatc2 Jun Ptprj Arhgap21 Etv6 Jun Crkl Arhgap21 Mapk9 Mapkapk2 Crkl Map3k7 Mapk9 Irf9 Tbk1 Map3k7 Tnfaip2 Stat2 Tbk1 Zc3h14 Tnfaip2 Sqstm1 Atf3 Zc3h14 Plk2/4 Sqstm1 Rbl1 Irf4 Plk2/4 Syk Mark2 Irf4 Irf8 Syk Samsn1 Tank Irf8 Dock8 Samsn1 Myd88 Sash1 Dock8 Stat4 Nfkbiz Sash1 Stat1 Stat4 Nfatc2 Cebpb Stat1 Etv6 Nfatc2 Nek7 Mapkapk2 Etv6 Irf9 Rgs1 Mapkapk2 Stat2 Irf9 Atf3 Phlpp Stat2 Rbl1 Atf3 Ppm1b Mark2 Rbl1 Tank Ikbke Mark2 Myd88 Tank Rgs2 Nfkbiz Myd88 Cebpb Nfkbiz Atf4 Nek7 Cebpb Rgs1 Mertk Nek7 Phlpp Rgs1 Map3k8 Ppm1b Phlpp Ikbke Ppm1b Ptpre Rgs2 Ikbke Atf4 Hat1 Rgs2 Mertk Atf4 Socs6 Map3k8 Mertk Ptpre Map3k8 Plagl2 Hat1 Ptpre Socs6 Dusp14 Hat1 Plagl2 Socs6 Ptpn1 Dusp14 Plagl2 Ptpn1 Dusp14 Runx1 Runx1 Ptpn1 Rela Rela Runx1 Pnrc2 Rela Pnrc2 Hmgn3 Pnrc2 Plk2 Hmgn3 Hmgn3 Plk2 Plk2 -1 Correlation 1 -1 Correlation 1 -1 Correlation 1 Candidate By Nicolas Chevrier, Harvard Medical School, USA Candidate Canonical Canonical Inflammatory (TF) Inflammatory Antiviral (TF)(TF) Antiviral (TF) The so-called dendritic cells (DCs) of the immune system are critical for the host’s defence against intruders. The DCs sense e.g. viruses via Toll-like receptors that in turn trigger a signalling cascade acti- Candidate vating antiviral genes. Knock-down of a variety of genes has recently shown that two Polo-like kinases Canonical (Plk2 and 4) are critical components of this antiviral signalling pathway as can be seen in the depicted Inflammatory (TF) correlation matrix with yellow indicating the highest level of correlation, and purple the lowest. Antiviral (TF) We are always looking for exciting scientific photos and illustrations! If you would like to have your image published, contact us at [email protected]. 4 04-7_News_1.13_RZ.indd 4 19.06.13 12:24 BOEHRINGER INGELHEIM FONDS FACTS FUTURA 28 | 1.2013 GOTTFRIED WILHELM LEIBNIZ PRIZE 2013 FOR IVAN DIKIC In recognition of his pioneering work on ubiquitin, Ivan Dikic is to receive one of the Gottfried Wilhelm Leibniz Prizes 2013, Germany’s most prestigious scientific awards. It comes with a grant of 2.5 million euros. Ubiquitin can be attached to other proteins in many different ways, leading to an almost unlimited number of possible structures. Ivan Dikic was one of the first scientists to decrypt the ubiquitin code. This tiny protein is involved in a wide range of pathophysiological processes, e.g. neurodegenerative disorders, immunological diseases and cancer. Ivan Dikic received his MD from the University of Zagreb in Croatia and obtained his PhD and postdoctoral training in New York. In 2002 Dikic joined Goethe University Frankfurt as professor of biochemistry. Currently, he is director of the Institute for Biochemistry II (IBCII) as well as of the recently founded Buchmann Institute for Molecular Life Sciences (BMLS) at Goethe University. Ivan Dikic held a Boehringer Ingelheim Fonds Research Award for Postdoctoral Fellows. Prof. Ivan Dikic: one of eleven recipients of the 2013 Leibniz Prizes, Germany’s most prestigious research funding prize. More information: www.dfg.de Photos: Deutsche Forschungsgemeinschaft (top); Dr. Gudrun Herzner (bottom) UNHYGIENIC HOSTS Cockroaches do not have the best reputation. Most people are repulsed by these creepy crawlies and they are considered public health pests that can carry dysentery, anthrax, salmonellosis, fungal diseases and other illnesses. The cockroach’s unhygienic lifestyle presents a problem not only to people but also to its predators. For example, the jewel wasp Ampulex compressa uses the American cockroach as a host for its larvae. The female wasp catches a cockroach, injects a venom to induce a lethargic state, and lays eggs in it. After hatching, the larvae feed on the living cockroach until pupation. The larvae of Ampulex compressa use a blend of antimicrobial substances to ensure that they can live in the cockroaches. The substances are secreted orally and sanitize the host from the inside. Researchers at the University of Regensburg have now analysed the composition of the secretion. When combined, the two dominant components – the isocoumarin (R)-(-)-mellein and the γ-lactone micromolide – have a broad spectrum of activity against gram-negative and gram-positive bacteria, mycobacteria, fungi and viruses. They thus ensure the larvae’s survival. These research findings may be of use to human beings: other studies have identified the lactone micromolide as a potential antibiotic against tuberculosis in humans. 5 04-7_News_1.13_RZ.indd 5 19.06.13 12:24 FUTURA 28 | 1.2013 FACTS BOEHRINGER INGELHEIM FONDS NEW SCIENTIFIC DIRECTORS AT IMB Professors René Ketting and Helle Ulrich. WHERE THE WILD THINGS ARE An essential question in understanding life on earth is why species are distributed across the planet as we find them today. The first attempt to describe the natural world in an evolutionary context was made in 1876 by Alfred Russel Wallace, the co-discoverer of the theory of natural selection. Until today, his map has been the backbone for our understanding of global biodiversity. Scientists from the University of Copenhagen have now produced a next-generation map depicting the organization of life on earth. Modern technology such as DNA sequencing and the vast compilation of hundreds of thousands of distribution records on mammals, birds and amphibians across the globe have made it possible to produce the new map. It shows the division of nature into 11 large biogeographic realms and illustrates how these areas relate to each other. It is the first study to combine evolutionary and geographical information for all known mammals, birds and amphibians – a total of over 20,000 species. The new map can be split into finer geographical details for each class of animals. Freely available, it will contribute to a wide range of biological sciences, as well as to conservation planning and biodiversity management. For more information about the foundation and its programmes, please visit REFERENCE www.boehringer-ingelheim-stiftung.de. Science 339 (2013): 74–8 (free access) Photos: Rene Ketting and Helle Ulrich, Institute of Molecular Biology (IMB) (top left) The Institute of Molecular Biology (IMB) at the University of Mainz, Germany, has appointed two new scientific directors: Profs. René Ketting and Helle Ulrich. Ketting is a leading molecular biologist focussing on the biology of non-coding RNAs. He will introduce C. elegans and the zebrafish as model systems at IMB to study mechanisms controlling development and disease. Helle Ulrich is internationally renowned in the field of DNA damage tolerance. Her research group investigates how genomes are maintained in a stable state in the face of a multitude of insults. Prof. Christof Niehrs, IMB’s founding director, is excited about Ketting and Ulrich joining IMB: ‘Both scientists have outstanding expertise in areas that are central to research at IMB.’ The Boehringer Ingelheim Foundation, BIF’s sister foundation, has endowed 100 million euros over a period of ten years to finance the scientific operation of the IMB at the University of Mainz. 6 04-7_News_1.13_RZ.indd 6 19.06.13 12:24 FACTS BOEHRINGER INGELHEIM FONDS FUTURA 28 | 1.2013 TINY MAGNETS MADE OF GOLD The map from The Geographical Distribution of Animals (1876) by Alfred Russel Wallace. What materials are magnetic? Most people are aware of iron and steel. Some know that nickel and cobalt are also magnetic, but almost no one would answer ‘gold’. That’s a shame, as scientists at the Helmholtz-Zentrum DresdenRossendorf (HZDR) have now discovered that gold can also be highly magnetic. Within the scope of a doctoral dissertation, researchers cultivated the microorganism Gold is magnetic – but only in tiny Sulfolobus acidocaldarius – a representative of the arparticles of just two nanometres. chaea – for biotechnological experiments. The cell wall of this unicellular organism consists of just one component, the S-layer. In a special procedure, this layer can be detached from the rest of the cell, providing researchers with a pure and highly stable matrix that can serve as a substrate for the formation of so-called nanoclusters. These may be used for example in nanocatalysis or in tiny electronic devices. The HZDR researchers treated the sulphurous protein envelope with a gold solution and then used a reductant to obtain metallic gold. The result: the gold formed nanoclusters on the protein substrate. The clusters were about two nanometres in size and magnetic. State-of-the-art X-ray scattering methods were used to demonstrate that the nanoclusters consisted of pure and highly magnetic gold. These properties could be the result of the gold’s interaction with the sulphur atoms of the Sulfolobus S-layer, the size of the particles, or the composition of the biological matrix. REFERENCE Photos: istockphotos/BanksPhotos (top right); Institute of Science and Technology, Austria/Sixt Group (bottom right) Physical Review Letters 109 (2012): 247203 HOW IMMUNE CELLS FIND THEIR WAY When immune cells patrol our systems, they leave the blood stream, move through tissues and re-enter the circulation system through lymphatic vessels. A group of researchers in Austria has found out how immune cells migrate within tissues and find their way back out again. The findings underline what has long been assumed but never experimentally proven in living tissue: that immune cells migrate along a concentration gradient of chemical cues which are immobilized in tissues. It was thought that the cells can sense their environment by either ‘touching’ (adhering to structural molecules such as connective tissue proteins via adhesion receptors) or ‘smelling’ soluble signal molecules with specialized surface receptors. Particularly solutes were believed to act as directional cues to guide the immune cells, as these are generally more concentrated closer to the production source. According to the new research paper, though, immune cells in the skin of mice use a mixed stratetgy. The researchers visualized both the immune cells (dendritic cells in the skin of mice) and the cue (chemokine CCL21) and watched how the cells move through tissues. They found that the chemokine is only produced by the lymphatic vessels, from which it distributes into the surrounding tissue, thereby creating a concentration gradient. According to the researchers, who drew quantitative maps of chemokine distribution and compared them to the migratory routes of cells, a cell can find the next lymphatic vessel by comparing the concentration of chemokine across the surface of the tissue and then crawling towards the higher concentration. This, however, only works if the chemokine is not solute: when the researchers released the anchoring of the chemokine to the tissue, the cells lost their way. Microscopic image of blood vessels (red), lymphatic vessels (green) and chemokine CCL21 (blue). REFERENCE Science 339 (2013): 328–32 7 04-7_News_1.13_RZ.indd 7 19.06.13 12:24 FUTURA 28 | 1.2013 FACTS BOEHRINGER INGELHEIM FONDS 8 08-12_Hauptartikel_3.12_RZ.indd 8 19.06.13 10:45 BOEHRINGER INGELHEIM FONDS FACTS FUTURA 28 | 1.2013 THE RHYTHMS OF LIFE By Michael Simm Like a finely tuned orchestra, our body’s organs, tissues and even single cells have their own melodies, yet together they stay in harmony with the outside world. Learning from animal models, chronobiologists have now identified most of the general principles and key players involved in time-keeping. Their findings extend beyond basic biology, though: ignoring your own rhythms and living out of sync with your internal clock can be dangerous for your health. Photo: avenueimages /Thomas Frey T hey always arrive within a few days between the end of April and the beginning of May: common swifts returning from their winter quarters south of the equator to their nesting destination. And to many European city dwellers, the bird’s short stay may well be a sight as pleasant as it is puzzling. Having travelled for thousands of kilometres, these birds will add at least another 900 kilometres per day throughout the nesting season, foraging incessantly in elegant manoeuvres until August, when they return to Africa to complete their annual migration cycle. The swift’s timing is both precise and flexible: these long-distance travellers seem to know the ideal time of arrival, a moment when they can find plenty of food for their young at their destination. Yet, they are also able to adjust their schedule and travel route when wet and/or cold weather strikes, thus maximizing the species’ chances of survival. But how exactly do they know when it’s time to go? Our distant ancestors from long-gone civilizations may have marvelled at the mysteries of animal migrations, the rhythms of animals and plants, the changes of the seasons, the comings and goings of days and nights, the patterns of high and low tide. They learned how to use these natural cycles to their advantage, not just adjusting to, but eventually even predicting the cycles. The French astronomer Jean Jacques d’Ortous de Mairan (1678–1771), however, is usually credited for being the first ‘chronobiologist’. In 1729, he observed that his mimosa plant kept folding its leaves in a daily rhythm even when sheltered from daylight in the darkness of de Mairan’s writing desk. Other scientists such as Carl von Linné (1707–1778) and Charles Darwin (1809–1882) reported similar phenomena and the latter even suggested the heritability of circadian rhythms, as opposed to the imprinting of a 24-h period by exposure to diurnal cycles. But it wasn’t until 1960 that chronobiology attained critical mass, owing to a Cold Spring Harbor symposium initiated by the German biologists Jürgen Aschoff (1913–1998) and Erwin Büning (1906–1990) and their US colleague Colin S. Pittendrigh (1918– 1996). Since then, the field has moved quickly from recording and describing the rhythms of life to unravelling the molecular clockworks that drive these processes. Clearly, unless you are a cave-dwelling olm or happen to live 200 metres below the ocean’s surface, the regular change from light to darkness constitutes the most important ‘zeitgeber’. In humans, it entrains and resets an inner clock that defines our circadian rhythm. This clock is usually set to 24 hours, but without the daylight 9 08-12_Hauptartikel_3.12_RZ.indd 9 19.06.13 10:45 FUTURA 28 | 1.2013 FACTS BOEHRINGER INGELHEIM FONDS Digging deeper into the mechanisms of time-keeping, in 1971 the American molecular biologist Seymour Benzer and his student Ron Konopka discovered a gene that affected daily rhythms in the fruit fly Drosophila and named it period (per). Mutated forms can lengthen (perL) or shorten (perS) a fly’s day or abolish its periodicity altogether (per0). Michael Rosbash and Jeffrey Hall cloned the gene in 1984 and were the first to propose the clock’s mechanism. The amount of per transcripts oscillates within a period of close to 24 hours, and its peak level is followed some 6 hours later by a peak in the corresponding protein, PER. Benzer and Konopka found that in a negative feedback loop PER forms a heterodimer with another clock-gene product (timeless, TIM) and that after translocation to the nucleus, the heterodimer inhibits its own activators, the transcription factors Clock (CLK) and Cycle (CYC). But this process is only part of the story of circadian rhythms and does not explain how fruit flies or humans with a free-running periodicity of 23.9 or 25 hours, respectively, are entrained to the day’s exact length of 24 hours. In Drosophila, that role is filled by the light-sensitive protein cryptochrome (CRY), which in the presence of light inhibits TIM. PER, then, is freed from the complex with TIM and becomes available for phosphorylation with yet another component of the molecular clock (Doubletime, DBT), clue, it would actually be close to 25 hours in most individuals, as which marks PER for degradation and thus sets the stage for the has been shown by experiments with subjects isolated for weeks in next cycle with new transcripts of the per gene. bunkers or as can also be observed in some blind people. Periodic changes can be seen in body temperature and heart- The same principles that have been discovered in fruit flies also beat, the functions of the lung and the liver, levels of hormones apply to mammals. Here, three counterparts of the per gene have such as cortisol, and the activity of the immune system’s macro- been found. Urs Albrecht, who heads a research group at Fribourg phages, for instance. Patients with arthritis tend to suffer in the University in Switzerland, showed that knockout mice without the morning, while most asthmatics have attacks at night. Blood pres- per gene don’t know what time it is. In addition, Per1 mutants were sure also goes down at night, but not in all people. Ideally, doctors unable to advance their inner clock in response to light exposure would adjust their prescribing habits accordingly. With a few ex- late at night, and Per2 mutants could not delay that clock when the ceptions, however, most of the chronobiologists’ findings have yet lights were turned on early in the night. In humans, the light-inducible genes PER1 and PER2 are essential for a normal resetting to enter clinical practice. of the clock. They are linked to the melanopsin receptors of the retBut what do we know about the biological clocks controlling our ina through the release of neurotransmitters in the SCN, which incircadian rhythm? In mammals, the light entering our eyes is first duce a signal cascade that eventually results in the transcription of registered by melanopsin, a pigment in specific nerve cells of the these genes. retina at the back of the eye. From these photosensitive ganglion From the SCN’s neurons in the brain, information has to be cells information is then transmitted through the optic nerve to relayed to subordinate central and peripheral clocks so that sleep, another group of neurons in the brain that serve as master pace- body temperature, blood pressure, heart beat, feeding behaviour makers. This suprachiasmatic nucleus (SCN) is an assembly of no and other functions can be properly aligned with the changing enmore than 20,000 cells. Proof of the crucial importance of the vironmental and social conditions around us. One important SCN comes from transplantation experiments in rodents that intermediate is the pineal gland, which receives input from the were pioneered by Michael Menaker and colleagues at the Univer- SCN to produce the hormone melatonin in response to darkness. sity of Virginia in 1990. They showed that hamsters and rats deAlbrecht and other researchers have discovered numerous prived of their SCN completely lose the circadian rhythm of their components of the inner clocks and new ones are being discovered running activities. These animals can regain their timing, how- at an astounding pace. In December 2012, Urs Albrecht, Steve ever, with a transplant from a donor animal. Interestingly, the re- Brown from Zurich University and the Laboratory of Achim cipients then display the donors’ individual variations in running Kramer at Charité Hospital (Berlin) published a paper in which habits. Human patients who have suffered damage to their SCN they described how the multifunctional nuclear protein NONO, are generally unable to keep normal sleep–wake cycles. which is another partner of PER, conveys circadian gating to the Periodic changes can be seen in body temperature and heartbeat, the functions of the lung and the liver, levels of hormones such as cortisol, and the activity of the immune system’s macrophages, for instance. 10 08-12_Hauptartikel_3.12_RZ.indd 10 19.06.13 10:45 FACTS BOEHRINGER INGELHEIM FONDS cell cycle, and that a lack of NONO surprisingly resulted in defective wound healing in mice. ‘It is now clear that generation and maintenance of circadian rhythms rely on complex interlaced feedback loops based on transcriptional and posttranscriptional events involving clock genes, kinases and phosphatases’, says Albrecht. Changes to any part of the inner clocks may force individuals to live out of tune: in humans, familial advanced sleep phase disorder (ASPD), which is associated with mutations in the PER2 gene, is one well-studied example. It makes affected people go to sleep at about 7 pm and get up before sunrise, usually around 4 am. In a recent genotyping study by Andrew Lim from the University of To- FUTURA 28 | 1.2013 ronto and colleagues, a single nucleotide polymorphism in PER1 was associated with clearly different sleep patterns among the 1,200 participants. Beyond sleeping patterns, there is also evidence to link clock gene dysfunction to mood disorders and addiction. Mouse mutants have been created that display low anxiety, mania and hyperactivity, reports Albrecht. The mood-stabilising agent lithium can reverse behavioural disturbances observed in clock mutant mice. This indicates that lithium might exert its effect via the circadian system. With regard to drug-seeking, mice lacking the Per1 HOW THE MOON INFLUENCES LIFE ON EARTH such as the valve movements depend only on nocturnal light of the permanently immersed stimuli. Acting on her curi- oyster Crassostrea gigas, the osity about the evolutionary movement patterns of Limu- origin of the hypothalamus, lus polyphemus (the American Tessmar-Raible had originally horseshoe crab) or the migra- focused with her team on spe- tions of the translucent acoel cific opsin-based photorecep- flatworm Symsagitiferra ro- tor cells in the medial region scoffensis, which regularly ex- of the worm’s forebrain. Her poses its symbiotic microalgae PhD students Benjamin Back- to the light at low tides in the fisch and Vinoth Babu Veedin shallow coastal area of Brittany. Rajan, however, fluorescently Photo: Max F. Perutz Laboratories labelled the worm’s melanopsin At the Max F. Perutz Labora- and uncovered additional eye- Frontal view of the four adult eyes of the bristle worm Platynereis tories, University of Vienna, lets in the head, as well as pho- labelled with green fluorescent protein. BIF alumna Kristin Tessmar- toreceptive cells in the ventral Raible confirms that there is no nerve chord and even in the Some people believe that the in Australia, and so do many evidence that lunar cycles sig- limbs of the worm. In a study moon not only orchestrates species of fish. The Greek phi- nificantly influence human ac- recently published in PNAS, the comings and goings of losopher Aristotle reported that tivities. ‘Life, however, evolved they show that these photore- the tides, but that it also influ- mussels and sea urchins around in the sea, and the study of ceptive cells develop and func- ences our bodies and even our the Mediterranean were ‘full’ in rhythms in our marine relatives tion independently of the eyes souls. However, most scien- full moon and ‘empty’ at new can shed more light onto our and that they may help orienta- tists reject this notion, pointing moon, which is true at least own evolutionary past’, she ar- tion. Tessmar-Raible’s team also to a lack of hard data to prove for some species whose go- gues. Tessmar-Raible is study- found similar photoreceptors any influence of the moon on nads swell and empty with the ing the links between lunar and in the lateral line of zebrafish, human behaviour. ‘There is no phases of the moon. circadian clocks in two marine thus establishing that non-ce- solid evidence that human biol- Today, contemporary chrono- model organisms, the bristle phalic photoreceptors outside ogy is in any way regulated by biologists are on the verge of worm Platynereis dumerilii and the eyes are more widespread the lunar cycle’, concludes Till understanding the molecular the marine midge Clunio mari- than had been assumed. This Roenneberg. Many marine or- bases of lunar rhythms in mar- nus. In a 1955 study, a relative opens the door to further stud- ganisms, however, do show en- ine animals. These discoveries of the famous palolo worms ies that may help our under- dogenous circalunar rhythms: are complemented by stud- (see main text), Platynereis standing of the evolution of the at least 30 species of corals ies of tidal cycles, which also dumerilii was the first organ- inner clocks not just in worms spawn in sync with the moon’s have a strong influence on ism for which the entrainment and fish, but also in our own phases at the Great Barrier Reef behaviour in some species, to a lunar cycle was shown to species. 11 08-12_Hauptartikel_3.12_RZ.indd 11 19.06.13 10:45 FACTS Activity of three Per genes in the suprachiasmatic nuclei (SCN) of mice. gene are no longer attracted to cocaine, while Per2 mutants show a hypersensitized response to cocaine. In mice, the amount and activity of monoamine oxidase A – an enzyme important in the degradation of the neurotransmitter dopamine – is modulated directly by Per2 and two other clock components, Bmal1 and Npas2. In humans, single nucleotide polymorphisms in these genes are associated with a specific type of depression (seasonal affective disorder), as has been shown by Timo Partonen from the Department of Mental Health and Alcohol Research at the National Public Health Institute in Helsinki, Finland. Carriers of the risk genotype were more than ten times more likely to develop symptoms than carriers of the most protective set of genes. More than 20 genes are now known to be part of the inner clock BOEHRINGER INGELHEIM FONDS The conveniences of civilization have made us independent of our environment, it seems. Heating and air conditioning keep our houses at the same temperature throughout the year; artificial lighting extends our days, and a significant part of the population work nightshifts, while numerous business travellers criss-cross the planet, quickly changing time and climate zones. Yet this lifestyle comes at a high price, as numerous studies have shown. ‘Chronic exposure to bright light – even the kind of light you experience in your own living room at home or in the workplace at night if you are a shift worker – elevates levels of a certain stress hormone (cortisol) in the body, which results in depression and lowers cognitive function,’ concludes Samer Hattar, professor of biology at the Krieger School of Arts and Sciences at Johns Hopkins University. Although his study was done on mice, it has been shown that in mice and humans the same type of retinal ganglion cells are activated by bright light and linked with the brain’s centre for mood, memory and learning. The switch to daylight saving time also leaves its mark and may disrupt the circadian clock’s seasonal adjustment, Roenneberg and his colleagues conclude from a survey of some 55,000 participants. One need not to go all the way ‘back to nature’, but some chronobiological events are so rewarding that they have become deeply embedded in cultural history. Each year in October or November, when the moon has just entered its third quarter, the palolo worm rises from the coral reefs surrounding the Samoan islands. More precisely, their segregated back ends wriggle their way up to the ocean’s surface, where they release sperm and egg packets that combine and grow to form the next generation of palolo worms. For a few hours only, the sea is full of these hind segments – and the locals walk out in the lagoon to harvest them by torchlight. The ‘caviar of the seas’, if not eaten raw on the spot, will end up in all kinds of dishes the day after. To the Samoans, it’s the most delicious food the ocean has to offer – and one in sync with life’s natural rhythms. in animals. Their numerous alleles provide a genetic basis for individual differences in time-related behaviours such as the preferred bedtime or duration of sleep, says Till Roenneberg, head of Human What´s your chronotype? Find out at www.euclock.org Chronobiology at the Institute for Medical Psychology at Ludwig Maximilian University (Munich). Roenneberg, who was one of the first biologists to study human chronotypes, has pointed out in his book Internal Time: Chronotypes, Social Jet Lag, and Why You’re so Tired (published in 2012) that early birds and night owls are born, not made. ‘Sleep patterns are the most obvious manifestation of the highly individualized biological clocks we inherit, but these clocks also regulate bodily functions from digestion to hormone levels to cognition’, he writes. Both scientists, Albrecht as well as Roenneberg, emphasize the importance of understanding and respecting our internal time. Albrecht likes to leave his lab to go jogging in order to recalibrate his inner clock. And Roenneberg advises people not to become enslaved by their alarm clocks, or else ‘social jet lag’ may result. The term describes a phenomenon experienced by many people who don’t get much sleep throughout the working week, then shift to sleeping longer and staying up later at the weekends. Photo: Prof. Albrecht FUTURA 28 | 1.2013 12 08-12_Hauptartikel_3.12_RZ.indd 12 19.06.13 10:45 Please understand that in the interest of our fellows, we publish only results online, not descriptions of ongoing projects. Therefore, this pdf continues with the section•Results•. BOEHRINGER INGELHEIM FONDS FELLOWS RESULTS The Boehringer Ingelheim Fonds does not intervene in the scientific work of its fellowship holders, who, together with their supervisors, decide whether new findings should make them alter their original aims. The extent to which intentions and results correspond at the end of the fellowship is demonstrated in the final report from the fellowship holders. Here we present a synopsis of their work and publications. FUTURA 28 | 1.2013 CATHERINE BRUN Studying terra-associated functions using transcriptionally inducible telomeres 30 MARTIN ETZRODT Monocyte responses during tumour progression 30 DAVID FERRERO Detection and avoidance of a carnivore odour by prey 30 LISA KÖNIGSMAIER The export apparatus of the Salmonella typhimurium type III secretion system 31 HEIKE RAMPELT The functional interplay of Hsp110 proteins with Hsp70 chaperones 31 BARBARA TREUTLEIN Mechanisms of eukaryotic gene expression at the single molecule level 31 29 29-30_Results_1.13_RZ.indd 29 19.06.13 10:59 FELLOWS FUTURA 28 | 1.2013 BOEHRINGER INGELHEIM FONDS STUDYING TERRA-ASSOCIATED FUNCTIONS USING TRANSCRIPTIONALLY INDUCIBLE TELOMERES MONOCYTE RESPONSES DURING TUMOUR PROGRESSION DETECTION AND AVOIDANCE OF A CARNIVORE ODOUR BY PREY cf. BIF FUTURA, VOL. 25 | 1.2010 cf. BIF FUTURA, VOL. 24 | 1.2009 cf. BIF FUTURA, VOL. 25 | 3.2010 CATHERINE BRUN MARTIN ETZRODT DAVID FERRERO Discipline: Molecular Biologist, MSc Discipline: Immunologist, MSc Discipline: Neurobiologist, MSc Institution: Institute of Biochemis- Institution: Massachusetts General Institution: Harvard Medical School, try, ETH Zurich, Switzerland Hospital/Harvard Medical School, Cambridge, MA, USA Supervisor: Prof. Claus Boston, MA, USA Supervisor: Prof. Stephen M. Azzalin Supervisor: Prof. Mikael Pittet D. Liberles Telomeres are repetitive nucleotide sequences at the end of chromosomes that protect them from fusion and degradation. During DNA replication, these regions are shortened but can subsequently be reelongated by the reverse transcriptase telomerase. Telomeres were originally thought to be transcriptionally silent but it is now known that they are transcribed into telomeric repeat-containing RNA (TERRA), which is a non-coding RNA that remains associated with the telomere. To study telomere transcription in vivo, we generated human cell lines containing telomeres that can be transcriptionally induced at will and named them tiTELs. Prolonged tiTEL transcription did not affect telomere length nor telomerase activity, thus contradicting the widespread hypothesis that TERRA acts as a general telomerase inhibitor. Furthermore, we showed that transcription increases telomere movements within the nucleus, possibly to favour their repair or stability. Our tiTEL cellular system represents a unique and valuable tool for understanding the functions associated with telomere transcription in vivo. Monocytes are essential for the innate immune response to pathogens and the repair of injured tissue. However, when mislocalized or overproduced, these white blood cells can also promote inflammatory diseases such as cancer. We aimed to identify factors that dictate the fate of monocyte populations during tumour progression in a murine model of non-small cell lung cancer. First, we found that monocytes residing in the spleen can relocate en masse to tumours and contribute to the population of so-called tumour-associated macrophages. Second, we discovered that overproduction of the peptide hormone angiotensin II in tumour-bearing mice amplifies haematopoietic stem and progenitor cells (HSPC) in the spleen, which allows this extramedullary tissue to maintain the monocyte supply throughout cancer progression. These findings could lead to novel therapeutic approaches that ‘tailor’ the responses mediated by monocytes by, for example, preventing the generation of specific cell populations that exhibit disease-promoting functions. Predator–prey relationships provide a classic paradigm for the study of innate animal behaviour. Odours from carnivores elicit fear and avoidance responses in rodents, although the sensory mechanisms involved are largely unknown. We identified a chemical produced by predators that activates a mouse olfactory receptor and produces an innate behavioural response. We purified this predator cue from bobcat urine and identified it to be a biogenic amine, 2-phenylethylamine. Quantitative HPLC analysis of 38 mammalian species indicated increased levels of 2-phenylethylamine in the urine of numerous carnivores, with some producing >3,000-fold more than the herbivores examined. Two prey species, rat and mouse, avoided 2-phenylethylamine, and enzymatic depletion of this amine from a carnivore odour indicated it to be required for full avoidance behaviour. Thus, a single, volatile chemical in the environment can drive an elaborate danger-associated response in mammals. PUBLICATIONS FARNUNG*, BO, BRUN*, CM, ARORA, R, LORENZI, Immunity doi:10.1016/j.immuni.2012.10.015 FERRERO, DM, WACKER, D, ROQUE, MA, BALDWIN, LE, AZZALIN, CM (2012) Telomerase efficiently elongates ETZRODT, M, CORTEZ-RETAMOZO, V, NEWTON, MW, STEVENS, RC, LIBERLES, SD (2012) Agonists for highly transcribing telomeres in human cancer cells. PLoS A, RAUCH, PJ, CHUDNOVSKIY, A, BERGER, C ET AL. 13 trace amine-associated receptors provide insight into One 7, e35714 (2012) Origins of tumor-associated macrophages and neu- the molecular basis of odor selectivity. ACS Chem. Biol. ARORA, R, BRUN, CM, AZZALIN, CM (2012) Tran- trophils. Proc. Natl. Acad. Sci. USA 109, 2491–6 7, 1184–9 scription regulates telomere dynamics in human cancer ETZRODT, M, CORTEZ-RETAMOZO, V, NEWTON, FERRERO, cells. RNA 18, 684–93 A, ZHAO, J, NG, A, WILDGRUBER, M, ET AL. (2012) PASHKOVSKI, SL, KORZAN, WJ, DATTA, SR, ET AL. * equal contribution Regulation of monocyte functional heterogeneity by miR- (2011) Detection and avoidance of a carnivore odor by 6a and Relb. Cell Rep. 1, 317–24 prey. Proc. Natl. Acad. Sci. USA 108, 11235–40 PUBLICATIONS PUBLICATIONS LI, Q, KORZAN, WJ, FERRERO, DM, CHANG, RB, ROY, ETZRODT, M, CORTEZ-RETAMOZO, V, NEWTON, A, DS, BUCHI, M, ET AL. (2012) Synchronous evolution of RYAN, R, PUCCI, F, SIO, S, ET AL. (2013) Angiotensin II an odor biosynthesis pathway and behavioral response. drives the production of tumor-promoting macrophages. Curr. Biol. doi:10.1016/j.cub.2012.10.047 DM, LEMON, JK, FLUEGGE, D, 30 29-30_Results_1.13_RZ.indd 30 19.06.13 10:59 FELLOWS BOEHRINGER INGELHEIM FONDS FUTURA 28 | 1.2013 THE EXPORT APPARATUS OF THE SALMONELLA TYPHIMURIUM TYPE III SECRETION SYSTEM THE FUNCTIONAL INTERPLAY OF HSP110 PROTEINS WITH HSP70 CHAPERONES MECHANISMS OF EUKARYOTIC GENE EXPRESSION AT THE SINGLE MOLECULE LEVEL cf. BIF FUTURA, VOL. 23 | 1.2008 cf. BIF FUTURA, VOL. 22 | 2.2007 cf. BIF FUTURA, VOL. 24 | 2.2009 LISA KÖNIGSMAIER HEIKE RAMPELT BARBARA TREUTLEIN Discipline: Structural Biologist, MSc Discipline: Biochemist, Diploma Discipline: Chemist, Diploma Institution: Research Institute of Institution: Center of Molecular Institution: Department of Chemis- Molecular Pathology/Institute of Biology Heidelberg (ZMBH), try, Ludwig Maximilian Molecular Biotechnology, University of Heidelberg, University (LMU), Munich, Vienna, Austria Germany Germany Supervisor: Dr Thomas C. Marlovits Supervisor: Prof. Bernd Bukau Supervisor: Prof. Jens Michaelis Many gram-negative bacteria contain the type III secretion system to transport toxins into host cells. The hallmark of this system is its core structure, the needle complex, which acts as a molecular syringe embedded in the bacterial membrane. Previous studies have shown that the assembly of the needle complex occurs in a step-wise manner, with the later steps requiring a group of conserved membrane proteins termed the export apparatus. However, very little is known about this process. Using cryo-electron microscopy and single particle analysis, we were able to gain insights into the role of the Salmonella typhimurium export apparatus proteins in building a secretioncompetent needle complex. We showed for the first time that the export apparatus associates directly with the needle complex and, more specifically, that a subpopulation of these proteins form a defined structure that initiates the assembly process. These results should ultimately be useful for the development of antibiotics that specifically target the type III secretion system. Hsp70 chaperones aid protein folding in a range of cellular contexts. Hsp110 proteins, divergent members of the same family, act as nucleotide exchange factors (NEFs) for Hsp70s. In my PhD project, I studied how these NEFs function and how their Hsp70like structure modifies their activity. Using a yeast prion as a model system for studying chaperone function in amyloid biology, I showed that the yeast Hsp110 Sse1 stimulates prion formation and stable propagation by its NEF activity and by directly stabilizing prionogenic conformations. Biochemical approaches then revealed that the metazoan Hsp70 system with Hsp110 efficiently reactivates proteins from pre-formed aggregates. This explains how disaggregation in metazoa – which lack a dedicated disaggregase – might function. My results thus provide insight into the unique roles of Hsp110s in the yeast and metazoan cytosol. PUBLICATION propagation in S. cerevisiae by two discrete activities. PLoS WAGNER, S, KÖNIGSMAIER, L, LARA-TEJERO, M, ONE 3, e1763 LEFEBRE, M, MARLOVITS, TC, GALÁN, JE (2010) ANDRÉASSON, C, RAMPELT, H, FIAUX, J, DRUFFEL- The open promoter complex (OC), which consists of RNA polymerase II (Pol II), a DNA bubble and transcription factors, has important roles in transcription initiation and RNA synthesis. Chromatin remodelling complexes facilitate formation of the OC by moving the nucleosomes, which compact genomic DNA. The molecular mechanisms of transcription initiation and nucleosome repositioning are poorly understood, and structural and biochemical analyses are limited by the flexibility of the multiprotein–DNA complexes involved. By combining single-molecule fluorescence resonance energy transfer (smFRET) with nano-positioning system analysis, I determined the 3-dimensional architecture of the OC and revealed global structural changes that occur during the transition between transcription initiation and elongation. I also found the location of the functional domains of a remodeller protein, chromodomain helicase DNAbinding protein 1 (Chd1), in a Chd1–nucleosome complex. My analysis of the structural dynamics of nucleosomes during repositioning in real time using smFRET showed that single remodellers can induce processive bidirectional translocation of nucleosomal DNA. My results contribute to our understanding of the mechanisms underlying eukaryotic gene expression. PUBLICATIONS SADLISH, H, RAMPELT, H, SHORTER, J, WEGRZYN, RD, ANDRÉASSON, C, LINDQUIST, S, BUKAU, B (2008) Hsp110 chaperones regulate prion formation and Organization and coordinated assembly of the type III se- AUGUSTIN, S, BUKAU, B (2010) The endoplasmic reticu- cretion export apparatus. Proc. Natl. Acad. Sci. USA 107, lum Grp170 acts as a nucleotide exchange factor of Hsp70 17745–50 via a mechanism similar to that of the cytosolic Hsp110. J. Biol. Chem. 285, 12445–53 RAMPELT, H, KIRSTEIN-MILES, J, NILLEGODA, NB, PUBLICATION CHI, K, SCHOLZ, SR, MORIMOTO, RI, BUKAU, B TREUTLEIN, B, MUSCHIELOK, A, ANDRECKA, J, (2012) Metazoan Hsp70 machines use Hsp110 to power JAWHARI, A, BUCHEN, C, KOSTREWA, D, ET AL. protein disaggregation. EMBO J. 31, 4221–45 (2012) Dynamic architecture of a minimal RNA Polymerase II open promoter complex. Mol. Cell 46, 136–46 31 29-30_Results_1.13_RZ.indd 31 19.06.13 10:59 FUTURA 28 | 1.2013 F O U N DAT I O N THE FOUNDATION The Boehringer Ingelheim Fonds (BIF) is a public foundation – an independent, non-profit institution for the exclusive and direct promotion of basic research in biomedicine. The foundation pays particular attention to fostering junior scientists. From the start it has provided its fellowship holders with more than just monthly bank transfers: seminars, events and personal support have nurtured the development of a worldwide network of current and former fellows. BOEHRINGER INGELHEIM FONDS THIRTY YEARS AGO: BIF’S BEGINNINGS Since 1983 BIF has celebrated many successes, grown and seen many changes 33 PROFILES What are they doing now? In this issue: Prof. Ivan Dikic, Dr Marc Erhardt-Singer, Dr Ulrike Grüneberg, Prof. Rüdiger Klein, Prof. Axel Nimmerjahn, Dr Till Strowig 33,34 WHO’S WHO AT BIF? Prof. U. Benjamin Kaupp answers the BIF questionnaire 34 PERSPECTIVES From scientist to consultant: interview with Dr Oliver Müller 35 A BIF FELLOW’S GUIDE TO ... ZURICH Carolin von Schoultz presents the largest city in Switzerland 36 NEW TRUSTEES FOR BIF Professors Thomas Braun and Christian Klämbt join the Board of Trustees 37 UPCOMING EVENTS Meeting of BIF’s Board of Trustees in Boston, MA, USA; annual meeting at Gracht Castle, Germany; Summer seminar in Hirschegg, Austria 37 32 32-37_Foundation_1_13_RZ.indd 32 25.06.13 12:30 BOEHRINGER INGELHEIM FONDS F O U N DAT I O N FUTURA 28 | 1.2013 PROFILES Prof. Rüdiger Klein, Photos: Mierswa Kluska Fotostudio (top right); Salk Institute for Biological Studies (middle right); Helmholtz Gesellschaft (bottom right) THIRTY YEARS AGO: BIF’S BEGINNINGS At the first meeting of BIF’s Board of Trustees in 1983, its members discussed seven applications for postgraduate fellowships, four of which were approved. Since then, BIF has celebrated many successes, grown and seen many changes. However, its core principles are still the same: support of people rather than scientific institutions, excellence in research and long-term commitment. T he Boehringer Ingelheim Fonds (BIF) was born on a chilly winter morning in 1983. But it was not only the temperature that was low on 12 January: the world was still suffering from a severe recession and an economic crisis worse in many ways than what we have experienced recently. And yet, the companies C.H. Boehringer Sohn and Boehringer Ingelheim International established a foundation for basic research in biomedicine. Even in such difficult times, the founders saw basic research as key for the future well-being of a country such as Germany. They also felt that private commitment with its greater flexibility should complement the state’s financial efforts. On 4 February of the same year, BIF was officially approved by the state authorities. Its purpose was to be (and still is) the elucidation of basic phenomena of human life using the approaches and methods of the natural sciences. Hubertus Liebrecht (1931–1991), a member of the shareholding family of the company Boehringer Ingelheim, had been the driving force behind the establishment of BIF. The DFG (German Research Foundation) and the Alexander von Humboldt Foundation had been powerful ‘birth attendants’. In Dr Hasso Schroeder, Hubertus Liebrecht found an enthusiastic personality who would become BIF’s first managing director. Due to Schroeder’s excellent connections in academia, BIF’s Board of Trustees included highly esteemed scientists right from the start, for example, Professors Wolfgang Gerok, Peter Sitte, Wolfgang Forth and Reinhard Schaper, as well as a representative of the DFG. A lot has happened since these early days – and the next issue of Futura will be a special anniversary edition dedicated to 30 years of nurturing excellent science juniors. director at the Max Planck Institute for Neurobiology in Martinsried, Germany, has been awarded a Synergy Grant from the European Research Council (ERC) amounting to 13.9 million euros – together with Professors Wolfgang Baumeister, FranzUlrich Hartl and Matthias Mann from the Max Planck Institute of Biochemistry. Rüdiger Klein’s department studies the role of receptors on the cell surface in the network of nerve cells throughout their entire lifespan. Rüdiger held a BIF postdoctoral fellowship from April 1988 to March 1990. Prof. Axel Nimmerjahn, assistant pro- fessor at the Waitt Advanced Biophotonic Center at the Salk Institute in La Jolla, USA, and holder of the Richard Allan Barry Developmental Chair, was awarded the 2012 National Institute of Health (NIH) Director’s New Innovator Award. Over a period of five years, he will receive 1.5 million dollars for his research on microglia, the resident immune cells in the brain. Axel was a BIF PhD fellow from August 2002 to January 2005. Dr Till Strowig was nominated junior research group leader by the Helmholtz Society, which is contributing 250,000 euros to his research group at the Helmholtz Center for Infection Research in Braunschweig, Germany. Till held a BIF PhD fellowship from March 2005 to October 2007. 33 32-37_Foundation_1_13_RZ.indd 33 19.06.13 12:29 F O U N DAT I O N FUTURA 28 | 1.2013 WHO’S WHO AT BIF? Prof. Ivan Dikic, dir- ector of the Buchmann Institute for Molecular Life Sciences and the Institute of Biochemistry II at Goethe University in Frankfurt, Germany, will receive the Ernst Jung Prize for Medicine 2013 for his groundbreaking work in understanding the role of ubiquitin in cellular signal regulation. The award is endowed with 150,000 euros and will be presented in May. Ivan Dikic held a Boehringer Ingelheim Fonds Research Award for Postdoctoral Fellows. Dr Marc Erhardt- Singer, BIF PhD fel- low from August 2007 until July 2010, was awarded the Elisabeth Gateff Prize of the German Genetics Society for his PhD thesis titled ‘Functional Analysis of Flagellar Type III Secretion in Salmonella enterica’. The award is endowed with 3,000 euros. Marc was also recently nominated junior research group leader by the Helmholtz Society, which is contributing 250,000 euros to his research group at the Helmholtz Center for Infection Research in Braunschweig, Germany. Dr Ulrike Grüneberg, group leader at the Department of Biochemistry at the University of Oxford, UK, has been appointed university lecturer at the Sir William Dunn School of Pathology and fellow of Keble College at the University of Oxford. She was also awarded a Medical Research Council Senior Non-Clinical Fellowship. From September 1995 until August 1998, Ulrike held a BIF PhD fellowship. PROF. U. BENJAMIN KAUPP Prof. U. Benjamin Kaupp was born in Tübingen, Germany. He is professor of molecular neurobiology at the University of Bonn, professor of biophysical chemistry at the University of Cologne, as well as scientific director of CAESAR (Centre of Advanced European Studies and Research, an institute of the Max Planck Society). Prof. Kaupp is a member of various scientific advisory boards, and has received numerous prizes, for example, the Humboldt Society’s prestigious Feodor Lynen Award. He is also a scientific member of the Max Planck Society and member of the German Academy of Science (Leopoldina). Prof. Kaupp joined BIF’s Board of Trustees in 1996. What do you like most about your work at BIF? The open, intellectually sharp, friendly, sincere, and often humorous discussions about the fellowships. What is your most remarkable experience connected with BIF? Many surprises in life are wearing off. I’m surprised, though, that after 16 years, I’m still enjoying my work with the BIF. What is your favourite activity? Hiking and biking. Where would you like to live? In Woods Hole – my second home, but only during the summer. What is your remedy for stressful situations? I become very quiet and speak with a low voice. What is your motto? To do what is right, even if people are not watching. What fault in others can you tolerate best? The faults that result from the German saying: ‘Der Geist ist willig, aber das Fleisch ist schwach’ – ‘The spirit is willing but the flesh is weak.’ Your advice for fellowship holders? Don’t take short cuts or detours. Avoid buzzwords and mainstream thinking. Stay away from people that have no sense of humour. Read Richard Feynman’s Caltech commencement address (1974) entitled ‘Cargo Cult Science’. Which scientific achievement do you admire most? I was fascinated and influenced by a paper by Howard Berg and Edward Mills Purcell about the physics of chemosensation (1977). It is a beautiful example of how far you can get with rigorous quantification and chemical-physical thinking in biology. Name one thing you couldn’t live without. Chocolate, Schokolade, Schoki … Photos: Deutsche Forschungsgemeinschaft (top left); Buttler-Design (top); BIF (middle left); Department of Biochemistry, University of Oxford (bottom left) PROFILES BOEHRINGER INGELHEIM FONDS 34 32-37_Foundation_1_13_RZ.indd 34 19.06.13 12:30 Photos: Deutsche Forschungsgemeinschaft (top left); Buttler-Design (top); BIF (middle left); Department of Biochemistry, University of Oxford (bottom left) F O U N DAT I O N BOEHRINGER INGELHEIM FONDS PERSPECTIVES FUTURA 28 | 1.2013 FROM SCIENTIST TO CONSULTANT In this section, we introduce BIF alumni from various scientific backgrounds and professional contexts. They describe their career paths and highlight important steps and decisions that helped them to reach their current position. INTERVIEW WITH DR OLIVER MÜLLER, CAPGEMINI CONSULTING ment. As a postdoc I therefore tried to spin off a biotech company from the Max Planck institution I worked at – my first dive into business matters. I filed patents, wrote business plans, secured grant money and negotiated with venture capital investors. In tough times for venture capital for biotechs and without any prospect of funding except for obtaining grant money, I left the spin-off project and joined the biotech company Amaxa in Cologne. As executive assistant to the CEO, I obtained an excellent insight into how a biotech company works. After leaving Amaxa, I wanted to work with a variety of life science businesses, and so I orn in 1970 in Pforzheim, Germany, joined the life sciences team of Capgemini Oliver Müller studied biochemistry in Consulting. Tübingen and Munich. In his PhD project, he explored the role of proteins involved In your view, what is the most important prein cellular membrane fusion. After several requisite for building a career in consulting? years in the biotech industry, he went into You definitely need strong analytical skills consulting in 2007, concentrating on pro- – which scientists literally have ‘in their jects for pharma, biotech and medtech genes’. However, consulting is also a people companies as well as for public sector cli- business and some of the biggest challenges ents. As head of healthcare, he leads in consulting projects are not on the soCapgemini Consulting’s activities in Ger- called rational level, but rather the emomany, Austria and Switzerland for hospi- tional or political level. Those must never tals, care providers and health insurers, as be underestimated and you must learn how well as for public sector health, research to deal with them. and government institutions. B What was your most rewarding experience in consulting? It is always rewarding when clients are satisfied and keep coming back. It means they trust you and appreciate what you have done to help them reach their goals. Did you ever regret leaving the lab? I am happy that my projects allow me to keep in close contact with the scientific world. My scientific background enables me to communicate with life sciences and healthcare clients on an expert level. For many projects in public research and government institutions, I feel that I can make a contribution to promoting science. So, to answer your question, I never regretted leaving the lab. Your advice for current fellowship holders? Find your passion and work hard, but keep a good work-life balance. Although consulting often means being at the client’s company and away from home, I can say from my experience that it is possible to combine a career in consulting with enough time for family and friends. There are many opportunities outside the academic world for bright minds where you can really make a difference. Be open to those opportunities. What was the biggest challenge in your From lab coat to business suit – what made career? Every project is a new challenge. A great amount of tact is required particularly in The findings from my PhD work were restructuring projects that involve organpotentially applicable in drug develop- izational changes in a company. you choose consulting instead of a career in academia? 35 32-37_Foundation_1_13_RZ.indd 35 19.06.13 12:30 F O U N DAT I O N FUTURA 28 | 1.2013 BOEHRINGER INGELHEIM FONDS 2 A BIF FELLOW‘S GUIDE TO ... ZURICH 4 3 1 Travelling is fun – especially if you get insider tips from locals! In each edition of FUTURA, one fellow shows you around his or her city. In this edition your guide is Carolin von Schoultz. She reports from Zurich, the largest city in Switzerland. FACTS & FIGURES NIGHTLIFE Countr y: Switzerland Population: About 392,000 Area: About 92 km2 Students: About 50,000 Famous for the Alps, cheese, chocolate, precision watches, Swiss knifes and direct democracy Websites: www.zuerich.ch, www.zuerich.com Mascotte: Locals love it for its weekly ‘Karaoke from hell’ and live concerts. Hive: Your place for house and electronic music until sunrise. Xtra/El Social: Discover how Salsa and Tango shape Zurich’s nightlife. Langstrasse: A whole quarter of multicultural and alternative bars and clubs. WHERE TO STAY BEST SIGHTS City Backpacker: In the heart of the old town, short walk to the main station. Kafi Schnaps: Affordable hotel, known for its cosy café downstairs. Zum guten Glück: A small hotel and famous pancake restaurant. Grossmünster/Fraumünster 2 : Two churches opposite each other on the river – look for the original Chagall windows. Niederdorf Street: Go here for drinks in funky bars and shopping in hip boutiques. Zürich-West: Check out the old railway viaduct 3 and the bars, cafés and individual shops. Sprüngli: The place for Swiss chocolate, the traditional Swiss breakfast and the divine Luxemburgerli pralinés. Rote Fabrik 1 : Great urban bar and cultural centre at the lake. El local: Pirate ship-like interior – sip your drink by the nearby river in summer. Winter: Sled down Uetliberg, go skiing nearby and reward yourself with a cheese fondue in the little Fondue Tram cruising through Zurich. Spring: Stroll along the lake 4 to Zürichhorn, take a ship tour, and visit the zoo. Summer: Swim in the Limmat river, enjoy free festivals such as Caliente. Autumn: Say hello to Hollywood stars at the Zurich Film Festival, visit the famous Schauspielhaus and the Kunsthaus art gallery (free on Wednesdays). Contributors wanted! If you would like to introduce your city to the readers of FUTURA, send an e-mail to [email protected] Name Carolin von Schou ltz Nationality German Age 26 Zurich, Institute of Pharmacolog y and To xicology Super visor Prof. Hanns Ulrich Zeilhofer University University of Carolin von Schoultz Photos: Livenet.ch (no 2); all others: Carolin von Schoultz RESTAURANTS ACTIVITIES 36 32-37_Foundation_1_13_RZ.indd 36 19.06.13 12:30 F O U N DAT I O N BOEHRINGER INGELHEIM FONDS NEW TRUSTEES FOR BIF FUTURA 28 | 1.2013 UPCOMING EVENTS 12–13 JULY 2013 Meeting of BIF’s Board of Trustees in Boston, MA, USA Christian Klämbt is professor of neuroProfessor Thomas Braun, director of the biology at the University of Münster in Max Planck Institute for Heart and Lung Germany. Our foundation’s Board of Trustees consists of six internationally renowned scientists, the speaker of the Board of Managing Directors at the company Boehringer Ingelheim, and – as a permanent guest – a representative of the DFG (German Research Foundation). The trustees work in an honorary capacity. Their most crucial function is scrutinizing applications for BIF’s fellowship programmes. They also review proposals for the International Titisee Conferences. Photos: Arteriogenesis Exp. NMR (top left); Westfälische Wilhelms-Universität (top right) Research in Germany. The Boehringer Ingelheim Fonds welcomes two new members to its Board of Trustees: Professors Thomas Braun and Christian Klämbt. Both joined BIF’s Board of Trustees in January 2013. Thomas Braun completed his MD in 1987 and obtained a venia legendi in biochemistry in 1993 at Hamburg University. From 1998 to 2004, he was director of the Institute of Physiological Chemistry at the University of Halle-Wittenberg. In 2004 he was appointed director at the Max Planck Institute for Heart and Lung Research in Bad Nauheim. Professor Braun is a member of the German National Academy of Sciences. He explores the molecular foundations of heart development and cardiac diseases and investigates cardiac regeneration and repair processes. Professor Christian Klämbt obtained his PhD in biology at the University of Freiburg, then worked as a postdoctoral research associate at the University of Cologne, Germany, as well as at the University of California in Berkeley. A group leader at the Institute of Developmental Biology, he obtained his venia legendi from the University of Cologne before he joined the University of Münster, where he is professor of neurobiology. In his research he focuses on developmental genetics and glial development. 19–21 JULY 2013 Annual meeting at Gracht Castle, Germany Meeting of former BIF PhD and MD fellows based in Europe. The meeting takes place at Gracht castle in Erftstadt/Liblar near Cologne, Germany. As BIF celebrates its 30th anniversary, this year will see a special Gracht seminar. For one it will host almost double the usual number of participants and boast a varied supporting programme. The talks will cover topics that have advanced substantially over the last thirty years and give an overview over these fast moving fields. As usual, the programme and the organizational details will be sent with the invitation. 10–16 AUGUST 2013 Summer seminar in Hirschegg, Austria Bidding farewell to Professors Lehmann and Herrlich. Professors Ruth Lehmann and Peter Herrlich left BIF`s Board of Trustees at the end of 2012 after having served 3 and 23 years, respectively. The foundation cannot thank them enough for their invaluable in-depth assessments of countless applications and their strong commitment to fostering young scientists. Having worked more than two decades in an honorary capacity on BIF’s Board of Trustees, Peter Herrlich has had the pleasure of seeing more than 20 BIF fellows whose cases he supported become professors. And this is only part of all he has done for the foundation, as BIF’s managing director, Dr Claudia Walther, points out: ‘With his passion for science, his impartial eye for scientific quality and a big heart for our fellows past and present, he was decisive in shaping and safeguarding the principles BIF stands for – excellent science, providing the academic freedom where ideas can grow, and a strong commitment to people.’ Seminar for PhD fellowship holders working in Europe. The meeting takes place in scenic Hirschegg, Austria. Participants will present their PhD projects and results. In addition to the scientific presentations, fellows will have the opportunity to discuss career subjects. The programme is supplemented by several guided hiking tours in the surrounding Alps. Need an update on upcoming events? Check our website at www.bifonds.de 37 32-37_Foundation_1_13_RZ.indd 37 25.06.13 12:31
