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MESSAGE FROMTHE CHAIRMAN

Recent years have been marked by unprecedented growthand development in the life sciences in areas such as genesequencing, protein interactions and molecular biology.

Research conducted during the last decade has resulted inimportant technological and conceptual advances, along withthe development of treatments and early stage cures fordiseases like cancer or neurodegenerative diseases.

The full sequencing of the human genome, and of a growingnumber of other living organisms, has heralded a new era inmolecular biology and genetics for human medicine. Although these discoveries have opened an unprecedentedpath toward medical advances, they have also revealed thatorganic, physiological and genetic mechanisms are far morecomplex than initially believed.

I am therefore particularly honoured that such an impressivepanel of scientists agreed to gather together at Ipsen’s newcorporate headquarters to lecture on the challenging andexciting perspectives of medical innovation.

Jean-Luc Bélingard,Chairman and CEO of the Ipsen Group

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FROMRMAN

Professor at the Collège de Franceand the Institut Pasteur, he is amember of the French Académie desSciences, the National Academy ofSciences US, the Institute of Medicineof the NAS. He discovered theallostery of proteins and isolated thenicotinic receptor of acetylcholine.Past president of the Comité Nationald’Ethique, he is the president of theCommission des dations, and thelaureate of many scientific prizes:médaille d’or du CNRS, Balzan prize,Louis-Jeantet Prize, BiotechnologyStudy Center of the New YorkUniversity school of Medicine award,Jean-Louis Signoret Prize of laFondation Ipsen, the NationalAcademy of Sciences award inneurociences (2007). He is also theauthor of several books including“l’Homme neuronal” and, recently,“Du vrai, du beau, du bien.Une nouvelle approche neuronale”.

Honorary professor at the Collège de France, secrétaire perpétuelleof the French Académie des Sciences, she is member of the NationalAcademy of Sciences US, the Royal Society, the Pontifical Academy of Sciences. She received several awards including the Médaille d’or du CNRS. Her research area has been mainly on the development of neural crest cells using originally a Chicken-Quail chimera modelshe had developed. She wrote several books including “Des chimères,des clones et des gènes” and “Les cellules souches porteusesd’immortalité”.

Jean-Pierre ChangeuxChairperson

Nicole Le DouarinChairperson

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In 1971, the United States President Richard Nixon called for a concentrated research initiative to conquer cancer,which was soon dubbed the War on Cancer. The Federal investment in cancer research rose dramaticallyand has been sustained throughout the ensuing decades. Yet thirty-seven years later, as deaths from cardiovasculardisease are declining, cancer threatens to become theleading killer in developed nations. Some critics claim thatwe have literally lost the war on cancer, blaming theresearch community for failing to focus on curing thedisease, instead indulging itself in molecular minutiae(1). But these Cassandras have it all wrong. By achieving amolecular understanding of how cancer originates and whyit often resists our best antidotes, we are poised to attackthe disease in ways that could not have been imaginedtwenty years ago. We have reduced malignant behavior to a relatively limited number of phenotypic perturbations ofthe cell(2). And we have uncovered the fundamental maladythat underlies those perturbations - a disturbance of twosorts of genes: proto-oncogenes, which are accelerators inthe cell; and tumor suppressor genes, which are brakes(3). The many and varied causes of cancer all somehow lead tojamming the accelerators and disabling the brakes. This fundamental simplification can now be applied to everyaspect of the cancer problem, including: determination ofcause; elucidation of genetic predisposition; early detection;stratification of disease; prediction of outcome; “magicbullet” therapies; personalization of therapy; and earlyprediction of therapeutic response. The prospects forsuccess in most of these applications rest in large measureon remarkable advances in genomic science. Efforts areunderway to create inventories of all the relevant genomicabnormalities in every form of human cancer(4). And thediscovery that the growth of cancers is probably fueled byoutlaw stem cells has uncovered a previously unknown “taproot” of cancer, offering new hope of cures by targetingtherapy to the outlaws(5). We have not closed the book oncancer for all time, but we are turning the pages veryrapidly. We can win the war on cancer: in the short term,with more effective therapies; and in the longer term, by interdicting the causes of cancer to prevent the disease(6).

J. Michael BishopUniversity of California,San Francisco

J. Michael Bishop is Chancellor, Arthur and Toni Rembe RockDistinguished Professor, University Professor, and Director of theG.W. Hooper Research Foundation at the University of California,San Francisco. Soon after arriving in San Francisco in 1968,he shifted his attention to Rous sarcoma virus, hoping to explorethe fundamental mechanisms of tumorigenesis. In 1970,he was joined by Dr. Harold Varmus. Together, they directed theresearch that led to the discovery of proto-oncogenes – normalgenes that can be converted to cancer genes by genetic damage.This work eventually led to the recognition that all cancer probably arises from damage to normal genes, and has providednew strategies for the detection and treatment of cancer.Drs. Bishop and Varmus have shared numerous awards for theirwork, including the 1989 Nobel Prize in Physiology or Medicine,and both have received the National Medal of Science.Dr. Bishop has devoted his subsequent research to the study ofproto-oncogenes – their functions in normal cells and their role in the genesis of cancer.He is a member of the National Academy of Sciences,the Institute of Medicine, the American Academy of Arts &Sciences, the American Philosophical Society, and the RoyalSociety of London. He is the author of more than 300 researchpublications, and of the book “How to Win the Nobel Prize:An Unexpected Life in Science”.

References(1) Begley, Sharon. We fought cancer… and cancer won.

Newsweek.com, Sept 6, 2008(2) Hanahan, D. and R.A. Weinberg. The hallmarks of cancer.

Cell 100:57-70 (2000)(3) Bishop, J. Michael. Molecular themes in oncogenesis.

Cell 64:235-248 (1991)(4) Jones, Sian et al. Core signaling pathways in human pancreatic cancers

revealed by global genomic analysis. Science 321:1801-1896 (2008)(5) Boman, B.M. and M.S. Wicha. Cancer stem cells: a step toward a cure.

J. Clinical Oncology 26:2795-2799 (2008)(6) Bishop, J. Michael. Cancer: what should be done? Science 278:995 (1997)

CREATING THE FUTURE:New Challenges in Biology and Medecine

MONDAY 19 JANUARY2009

ABSTRACTS

CAN WE WIN THE WAR ON CANCER?

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Innate immunity is a first line defensemechanism against infections which is sharedby all metazoans (and metaphyta). Adaptive immunity has appeared in theancestors of cartilagenous fish, probablysome 450 millions years ago, and contributesto the host defense solely in Vertebrates,which represent some 5 % of all existantanimal species. In these species, innate immunity, in addition to its directroles against microorganisms, activates and orients the adaptive responses.Studies in model organisms, such asDrosophila melanogaster, have led in recentyears to a basic understanding of innateimmunity in the absence of adaptivedefenses. The receptors for bacterial andfungal cell wall components (essentiallypeptidoglycans and glucans) have beenidentified. Two prominent intracellularsignaling cascades are activated downstreamof these receptors: the Toll pathway duringfungal and Gram-positive bacterial infections,and the immune deficiency (IMD) pathwayduring Gram-negative bacterial infection.These cascades act upon transcription factorsof the NF-kappaB family which ultimatelycontrol the expression of hundreds ofimmune genes the products of which concurto fight off the infections.

Genome sequencing has recentlyrevealed that most of the players(genes) of the innate response ofDrosophila are already present in asancient animal forms as sponges andcnidaria, suggesting that the innateimmune response as we now see it in Drosophila has appeared withmulticellularity. Importantly, all thegenes involved in the host defense of the fly, have homologues (or very similar counterparts) in theimmune response of mammals: this isin particular the case for the Tollreceptors initially discovered in flies.

Jules HoffmannInstitut de Biologie Moléculaire et Cellulaire,Strasbourg

J. Hoffmann is a Research Professorwith CNRS at Strasbourg and currentlythe President of the French Académiedes Sciences. He is also a Member ofthe National Academy of Sciences USAand of several European Academiesand a recipient of the Cooley, Koch andBalzan Prices. He has devoted hisscientific career to the study of innateimmunity with Drosophila as a modelsystem. J. Hoffmann and his colleaguesare credited with the discovery of therole of Toll receptors in innate immunedefenses and the deciphering of thesignaling cascades activated duringfungal, bacterial, viral and parasiticinfections in model systems.

PHYLOGENETICPERSPECTIVES OF INNATE IMMUNITY

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The pituitary gland is the master regulator ofthe endocrine systems of the body, secretinghormones that regulate many importantbody functions such as growth andmetabolism, reproduction and lactation, and responses to stress. The pituitary is itselfcontrolled by specialized neurons in a regionof the brain called the hypothalamus. These neuroendocrine neurons release theirproducts into a “private” blood supply, thehypophysial portal system, which carriesthem from the brain to the pituitary gland. In this way, the brain controls our hormonesystems to maintain normal homeostasis andto respond to changing demands throughoutlife. New developments in physiologicaltransgenesis and imaging make it possible to view and manipulate neuroendocrinesystems in living animals, looking both “up”and “down” this system. Looking towardsthe brain gives insights into the secretionsand activities of these specialized neurons,how they act together to integrate signalsfrom different regions of the brain and fromthe periphery, and to find out what theircommand outputs are, reaching theirpituitary target cells, and beyond. Lookingtowards the pituitary reveals a complexorganization of cell networks that respondto incoming signals by secreting theirhormone products in coordinated patterns.The pituitary gland is remarkably plastic, withresident stem cells in the adult gland that can replenish all of the different cell typesaccording to changing physiological demands.Thus the portal system carries neuroendocrinecascades of signals that amplify and convertsmall neuronal messages to large hormonalsignals, coded in both frequency andamplitude of their sounds and silences, towhich the rest of the body is listening.

Iain C.A.F. RobinsonMRC, National Institute for Medical Research,London

After postgraduate training in Oxford and Denmark,Iain Robinson joined MRC’s National Institute forMedical Research (NIMR) at Mill Hill, London, wherehe is Head of the Division of MolecularNeuroendocrinology, and Director of NIMR. He is aVisiting Professor at University College, London andFellow of the Academy of Medical Sciences.He has also worked in the pharmaceutical industryand co-founded a Biotech company.His research interests are in development, growthand metabolism in health and disease.

CREATING THE FUTURE:New Challenges in Biology and Medecine

MONDAY 19 JANUARY2009

ABSTRACTS

NEUROENDOCRINE REGULATION:A VIEW FROM THE PORTAL

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At the beginning of the third millennium,man has an opportunity to fulfill thecherished goal of improving the lot ofhumankind. Newer modalities of medicineare being practiced and daily newbreakthroughs are being reported. I wouldlike to talk about gene therapy, a form ofmolecular medicine, which will have a majorimpact on human health. At present, genetherapy is being contemplated for bothgenetic and acquired diseases. These includehemophilia, cystic fibrosis, diabetes, cancer,Parkinson’s, Alzheimer’s, etc. A primerequirement for successful gene therapy isthe sustained expression of the therapeuticgene without any adverse effect on therecipient. A highly desirable delivery vehiclewill be the one that can be generated athigh amounts, integrate in non dividing cellsand have little or no associated immuneproblems. We have generated thirdgeneration lentiviral vectors with expandedhost range that can introduce genes in avariety of cells. Thus our current lentiviralvectors are devoid of six viral genes andtherefore we consider them to be safevectors. By using third generation lentiviralvectors we can introduce genes directly intobrain, liver, muscle, hematopoietic stem cells,and more recently retina and a number of

tumor cells. Our data shows thatlentiviral vectors cannot only efficientlydeliver genes, but also have long termsustained production of the foreignprotein. We have not observed anyuntoward immunological consequencesdue to the vector.My talk will discuss in detail the use of vectors for a wide variety of geneticand acquired diseases. Additionally I will discuss the use of lentiviralvectors for transgenesis, studyingcomplex biological systems. I will alsodiscuss the use in reprogrammingsomatic cells.

Inder VermaLaboratory of Genetics,The Salk Institute,La Jolla, California

Inder Verma, American Cancer SocietyProfessor of Molecular Biology in theLaboratory of Genetics at The SalkInstitute is one of the world's leadingauthorities on the development and useof engineered viruses for gene therapy.He received a master's degree fromLucknow University, India, and a PhDfrom The Weizmann Institute of Sciencein Rehovoth, Israel. Dr. Verma waselected to the National Academy ofSciences, American Academy of Artsand Sciences, and the AmericanPhilosophical Society.

GENE THERAPY: 25 YEARS OF UPS AND DOWNS

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Stem cells are loosely defined as self-renewingprogenitor cells that can generate one ormore specialized cell types. In vertebrates, stem cells are traditionallysub-divided into two groups. The first groupconsists exclusively of embryonic stem (ES)cells. These cells, which are derived from theinner cell mass of the blastocyst, are capableof generating all differentiated cell types inthe body. ES cells, in turn, generate thesecond group, which are organ- or tissue-specific stem cells. An example of this secondgroup is the neural stem cell, whichgenerates all of the cell types of the nervoussystem. In most organs, stem cells arepresent through adulthood, albeit in smallnumbers. In some organs, like the brain,these stem cells can be isolated from tissues,grown in culture, and then induced todifferentiate, either in vitro or aftertransplantation in vivo. However, it is notclear whether ES cells or tissue- specificcells, other than in the hematopoetic system,can be transplanted clinically to replacediseased or damaged human cells.It has long been believed that organ-specificstem cells are restricted to making thedifferentiated cell types of the tissue inwhich they reside. In other words, these cellshave irreversibly lost the capacity to generateother cell types in the body. This concept ofrestriction has recently been challenged,opening up the possibility that tissue-specificcells might be reprogrammable.I will report on efforts to understand themolecular and cellular bases of cell fatedetermination of ES cells and of tissue-specific stem cells; in addition, I will addressthe issue of reprogramming adult cells. I willdraw from results in the nervous system toillustrate the progress being made to revealhow stem cell biology can be valuable to theunderstanding of fundamental issues of brainfunction as well as to the modeling ofhuman neurological disease.

Fred H. GageLaboratory of Genetics, The Salk Institute,La Jolla, California

Fred H. Gage, Ph.D., a Professor in the Laboratory of Genetics, joined The Salk Institute in 1995.He received his Ph.D. in 1976 from The JohnsHopkins University. Dr. Gage's work concentrates onthe adult central nervous system and unexpectedplasticity and adaptability to environmentalstimulation that remains throughout the life of allmammals. In addition, his studies focus on thecellular, molecular, as well as environmentalinfluences that regulate neurogenesis in the adultbrain and spinal cord.Prior to joining Salk, Dr. Gage was a Professor ofNeuroscience at the University of California, SanDiego. He has won numerous prizes and awards forhis work including La Fondation Ipsen Prize forNeuroplasticity and recently the Keio MedicalScience Prize; serves on many health relatedboards, and was President of the Society forNeuroscience. He is a Fellow of the AmericanAssociation for the Advancement of Science,a Member of the National Academy of Sciences and the Institute of Medicine, and a Member of the American Academy of Arts and Sciences.

CREATING THE FUTURE:New Challenges in Biology and Medecine

MONDAY 19 JANUARY2009

ABSTRACTS

GENERATING BRAIN CELLSFROM STEM CELLS

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I will consider a general molecularmechanism, which emerged from studies of Aplysia and mice whereby a transientshort-term memory is converted into astable, self-maintained, long-term memory. I will then consider cellular mechanisms inthe mouse whereby a long-term explicitmemory for space is perpetuated by meansof selective attention during acquisition.

Finally I will consider a novel molecularmechanism for self-sustaining perpetuationof memory storage.

ON THE PERSISTENCE OF MEMORY STORAGE

Eric R. KandelColumbia University,New York

Eric R. Kandel, M.D., is UniversityProfessor at Columbia, Fred KavliProfessor and Director, Kavli Institutefor Brain Science and a SeniorInvestigator at the Howard HughesMedical Institute. A graduate of HarvardCollege and N.Y.U. School of Medicine,E. Kandel trained in Neurobiology at theNIH and in Psychiatry at HarvardMedical School. He joined the faculty ofthe College of Physicians and Surgeonsat Columbia University in 1974 as thefounding director of the Center forNeurobiology and Behavior. Recipient ofmany awards, including the 1983Lasker Prize, the 2000 Nobel Prize, theNational medal of Science, and theJean-Louis Signoret Prize of LaFondation Ipsen, he is a member of theNational Academy of Sciences USA andthe French Académie des Sciences.He recently published his autobiography:“In search of memory”.

Eric Kandel’s research has beenconcerned with the molecularmechanisms of memory storage inAplysia and mice. More recently, he hasstudied animal models in mice ofmemory disorders and mental illness.

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Stanislas DehaeneCollège de France, ParisINSERM-CEA Cognitive Neuroimaging UnitSaclay

Stanislas Dehaene is professor at the Collège de France, wherehe holds the chair of Experimental Cognitive Psychology. He is thehead of the INSERM-CEA Cognitive Neuroimaging Unit atNeuroSpin in Saclay, just south of Paris - France’s advancedneuroimaging research center. His research investigates theneural bases of human cognitive functions such as reading,calculation and language, with a particular interest for thedifferences between conscious and non-conscious processing.He is a member of the French Académie des Sciences and of thePontifical Academy of sciences and the author of several books,including: La bosse des maths and Les neurones de la lecture.Laureate of the Jean-Louis Signoret prize of La Fondation Ipsenand the Louis D. prize of the Institut de France, the Heineken prizefor cognitive science.

MONDAY 19 JANUARY2009

ABSTRACTS

CREATING THE FUTURE:New Challenges in Biology and Medecine

CAN WE UNDERSTAND HUMANCONSCIOUSNESS?

For many years, consciousness wasconsidered outside of scientific investigation.Around the 1980s, however, under theimpulsion of Larry Weiskrantz, Tim Shallice,Michael Posner, Francis Crick, ChristophKoch, or Bernard Baars, the cognitive andneural architectures of consciousness becamea prominent focus of experimentalinvestigation. Building upon this work, Jean-Pierre Changeux and I proposed asimple framework, the global neuronalworkspace, which predicted thatconsiderable cerebral processing was possibleunder non-conscious conditions, but thatconscious access would correspond to thenon-linear ignition of a distributed network,dominating in prefrontal and parietalcortices, which serves to broadcastinformation and make it reportable.I will present a series of experiments,performed with Laurent Cohen, Antoine DelCul, Raphaël Gaillard and Lionel Naccache,that use masking to test the model. Wecreated minimal contrasts betweensubliminal and conscious processing of visualstimuli, and tracked the ensuing brainactivation using event-related potentials andintracranial recordings. Non-consciousprocessing was observed in multiple corticalareas within an early time-window,accompanied by induced gamma-bandactivity, but without coherent long-distanceneural activity, suggesting a quicklydissipating feed-forward wave. By contrast,conscious processing of unmasked wordswas characterized by four simultaneousneurophysiological markers: sustained voltagechanges, particularly in prefrontal cortex,large spectral power increases in the gammaband, increases in long-distance phasesynchrony within the beta range, andincreases in long-range Granger causality.We argue that all of these measures providedistinct windows into the same “ignited”state of conscious processing. Thisknowledge is now being applied to themonitoring of non-conscious integrity andconscious states in non-communicatingpatients.

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