Bernd-Uwe retires - EMBL Grenoble

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interviewRight: “There are thousands of proteins which make hundreds of interactions; theremay also be hundreds of proteins which make thousands of interactions”.(Figure prepared with the STRING server (http://string.embl.de))Turn off those kinase cascades!EMBL Heidelberg team leader Toby Gibson goes public with a crusadeagainst the consequences of overly simplistic perspectives following thepublication of an opinion piece in Trends in Biochemical Sciences (TiBS)Toby, what’s all this about?It’s an ongoing debate about the issue ofoversimplification in biology. You have to bereductionist in science in order to be able todevise experiments. You need to fix manyaspects of a system and then you perturbjust one thing and see what happens. Later,you might forget that you’ve fixed so muchthat you’re not invoking so many of thethings that could happen – that could playroles in overall regulation – because you’reonly looking at one aspect.Is this a new idea?Physicist Niels Bohr considered truth andclarity to be complementary. The term cooperativity– multiple binding interactionsthat influence each other positively or negatively– is quite old. Classical biochemistsworking on enzymes have known about itfor a long time. You can’t have biologicalcomplexity without cooperativity, and youcannot have robustness without a complicatedsystem. The only way to be robust iswith complicated decision-making, notbased on a single parameter.What consequences does this have?Firstly, that kinases cannot cascade. If youstart seeing cell regulation as highly networked,highly cooperative and also highlyredundant, then it’s not hard to see thatthere’s a need in certain parts of medicinefor multi-drug therapy. Cancer cells removecooperativity to simplify key pathways: Theyactually become less robust than healthycells. With one drug you may kill most cancercells; but in others, there’ll always be mutationsin there that can circumvent it anduse another way to achieve the same thing.In multi-drug therapy, you try to hit everythingthat a cancer cell regards as important.If you knew enough about a cancer cell –not just that it gets a growth factor signal,but about its pathways that suppress apoptosis,and about its metastasis – and you hitthe right pathways for this cancer, then youhave a chance of knocking out the whole cellpopulation. The corollary is that the healthycells are more robust and may survive thetherapy much better than the cancer cells.So what can be done about it?Currently, cell system models are too simple.If wet lab people don’t tell the modellers thatsystems are cooperative, of course they won’tmodel them that way. But people on thebench say ‘I’ve just found that a binds to b,and that’s all I need to know. I don’t need toknowthat anothertenmolecules arebinding to modulate that.’ In fact you do, butthey rather hope the system is simpler, becausethen they’ve understood it.There’s a story I like to tell: it’s the inaugurallecture for the first ever cellular systemsbiology course. The eminent professor kicksthings off with the old joke, “Bacteria arejust a bag of enzymes!” The students are delighted:“Hey, I know how to model that.”And so it has been ever since, the larger eukaryoticcells then simply being modelled asa bigger bag with some pockets in it.How will you be addressing this issue?There’s a standard that defines how we putinteraction data into the computer, and thishas nothing about cooperativity in it, so wecan’t capture at the very first step that someonehas found cooperativity. One of thethings I’m hoping to do next year is to startworking on that. I’ve already been talking tostandards people at the EBI about it.You can read Toby’s article atwww.cell.com/trends/biochemical-sciences/fulltext/S0968-0004%2809%2900142-XHow can we feed the world?Scientists, journalists and politicians discussthe future of sustainable agricultureA record number of 270 participants heardabout the contribution plant science canmake to the global challenge of food securityin a growing world population at theEMBO/EMBL Science & Society conferenceon 6-7 November at EMBL.A farmerfrom theIndian stateofMaharashtrain a fieldplanted withgeneticallymodified BTcottonThe two-day event, ‘Food, Sustainabilityand Plant Science: A Global Challenge’looked at food shortage, which – next to climatechange – is the greatest challenge facingthe world. To stay on top of the worldwidefood supply for nine billion people in2050, the production of staple crops has toincrease by at least 50 per cent. Alreadytoday, more than one billion people in theworld are hungry. The green revolution,which started in the fifties, tripled the worldfood production, but resulted in a dependenceon very few strains of major foodcrops. What’s worse, 40 percent of the arableland has become seriously degraded and infertileand biodiversity has sharply declined.According to Sir David Baulcombe, Universityof Cambridge, the existing agriculturalproduction system is operating close tofull capacity. The threatened worldwidefood supply calls for innovative technologiesto breed new strains of robust and efficientplants: crops resistant to flooding, draught,salination and pests as well as high yieldingcrops enriched with micronutrients and vitamins.Pamela Ronald of the University ofCalifornia, Davis, said: “There are notenough breeders in general. It’s almost likewhere we were ten years ago with bioinformatics.”Plant breeders and researchers deplorethe lack of young scientists interestedin these topics.European public and policy makers largelyignore the impending crisis. As a consequence,public funding and support forplant and agricultural research are low andplant breeding is left to big industry thatholds a quasi monopoly and most of the exclusivecommercial rights. Sir DavidBaulcombe called for scientists to becomepolitical and alert policy makers and thepublic to the crisis. – G. Wallon & Y. Kaul8EMBL&cetera • December 2009
When biology meets mathsResearch from Jan Ellenberg’s group atEMBL Heidelberg has revealed that fractals– fragmented shapes made up of reducedsizecopies of the whole – could be usefulmathematical tools to describe the behaviourof molecules in the nucleus.The nucleus of eukaryotes is enriched inDNA, proteins and RNA, and is thusthought to be a crowded area. In vitro, it hasbeen shown that molecular crowdingstrongly affects protein dynamics butwhether this is also relevant in vivo remainsunclear. In a study published on 16 Decemberin the EMBO Journal, postdocsSébastien Huet and Aurélien Bancaud followedthe movement of fluorescent moleculesin living cells, and saw that theymoved as if having to navigate obstacles.Comparing the pattern of movement of different-sizedmolecules, they found that largemolecules moved according tothe same rules as small ones.This result suggested thatthese molecules were ‘seeing’the same crowded environment,regardless of scale; thattheir environment, in fact, wasfractal. “It’s like a system ofbranched channels resemblinga coastline,” says Jan, who’sGender-bending miceEMBL researchers have uncovered thegene responsible for keeping females femalein a study published on 11 Decemberin Cell.In humans and most other mammals, anindividual’s sex is determined by its sexchromosomes: females have two X chromosomes,and males have an X and a Y.Scientists had long assumed that the femalepathway – the development ofovaries and all the other female traits –was the default: if an embryo had a genecalled Sry, which is located on the Y chromosome,it would develop into a male; ifnot, then the result would be a female.A gene called Foxl2, which is located ona non-sex chromosome and thereforepresent in both sexes, was known to playan important role in the female pathway,but its precise function remained elusive.When Mathias Treier’s group turned offthis gene in the ovaries of adult femalemice, they found that cells in the ovariesturned into cells typically found in testes.“We were surprised,” says Mathias, whohead of the Cell Biology and BiophysicsUnit.The team then watched how different proteinsmoved and bound to euchromatin andheterochromatin. They found that euchromatinshows a high fractal dimension,which means it exposes a large, rough surfaceto the molecules. In contrast, heterochromatin’slow fractal dimension makesit smoother and flatter, with a smaller exposedsurface.“This could help to explain how the celltweaks the behaviour of the proteins thatcontrol DNA,” says Sébastien. “The nucleusmight be able to switch the way proteinslook for targets on chromatin simply by alteringthe fractal structure of chromatin.”Left: A cell displays chromatin (green) and amolecule used for tracking (red). Right: A closerlook at the fractal architecture of chromatincollaborated with colleagues from theMRC’s National Institute for Medical Research(NIMR), in Mill Hill, UK, for thestudy. “We expected the mice to stop producingoocytes, but what happened wasmuch more dramatic: somatic cells whichsupport the developing egg took on thecharacteristics of cells which usually supportdeveloping sperm, and female hormone-producingcells switched to themale type.” This challenges the long-heldassumption that the development of femaletraits is a default pathway, showingthat the male pathway needs to be activelysuppressed, and also grants a valuable insightinto how sex determination evolved.These findings will have wide-rangingimplications for reproductive medicineand may help to treat sex differentiationdisorders in children or understand themasculinising effects of menopause onsome women. The study is discussed byMathias in a Cell ‘PaperFlicks’ video onYouTube at www.youtube.com/watch?v=-oL7RKUNchY.obituaryWe regretfully inform the EMBL communitythat our colleague, Göran Wikell, diedon 21 November in Heidelberg.Göran came to EMBL in 2001, first as partof the Swedish Audit Group for EMBL,EMBC and EMBO and then, as of 2004, asan external Auditor for EU Grants. Between1969 and 2005 he held various senior positionsat the Swedish National Audit Office.Göran was a highly regarded professionalwith a strong sense of duty and commitment.He quickly grasped the spirit ofEMBL and embodied it in his work and actions,and we had the privilege to knowGöran as a kind and helpful colleague witha good sense of humour. He will be greatlymissed.Flu fighterA new EMBL spin-out company, SaviraPharmaceuticals (www.savira.at), will focuson the development of drugs for the treatmentof influenza.Co-founded in September by EMBL andthe Vienna-based biotech companyonepharm Research and DevelopmentGmbH, Savira will build on the breakthroughresults from Stephen Cusack´s labwhere they identified the molecular architectureof the cap-binding domain in thePB2 in the PA subunit of the influenza viralpolymerase.These findings, in which Darren Hart’sgroup at EMBL Grenoble and EMBL Heidelberg’sChemical Biology Core Facilitywere also involved, open new avenues forthe structure-based development of anti-influenzadrugs, targeting the viral polymeraseto selectively stop the reproductive cycle.Savira’s development pipeline of selective inhibitorswill be fuelled from three differentmedicinal chemistry programmes and willdraw on the know-how and intellectualproperty of the founders. “We believe thatSavira is the perfect vehicle to translate ourbasic research results into urgently neededdrug candidates to combat both seasonaland pandemic influenza,” says Martin Raditsch,Deputy Managing Director of EM-BLEM, EMBL’s technology transfercompany.Savira, which is based in Vienna, received€1m support from the Austria Wirtschaftsservice(AWS) and was awarded third placeby the City of Vienna Future Award (WienerZukunftspreis 2009) in the category ‘Newcomersand Start-ups’.EMBL&cetera • December 20099
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