Stem Cells - Therapies for the future? - Projects catalogue; haematopoietic stem ... from basic biology to development of preclinical ... graft-versus-host disease. The work focuses

L i f e S c i e n c e s D i s c u s s i o n P l a t f o r m

The European Commission invites a pluralistic and informative debate between researchers and a wide range of representatives of society on

STEM CELLSTHERAPIES FOR THE FUTURE?

PROJECTS CATALOGUE

Charlemagne Building – Brussels, Belgium 18 - 19 December 2001

U N D E R T H E A E G I S O F T H E L I F E S C I E N C E H I G H L E V E L G RO U P EUROPEAN COMMISSION – RESEARCH DG – LIFE SCIENCES DIRECTORATES

European CommissionResearch DG / Life Sciences Directorates

What are stem cells? Stem cells are cells that have yet to become fully differentiated (specialised).They havethe capacity both to self-renew (to yield through division cells identical to themselves)and to differentiate (to generate more specialised cells).They are present at all stagesof life - embryonic, foetal, juvenile, adult - but tend to decrease in number with age.

Stem cells are precursors to more specialised cells. Some have the potential to generateevery cell type in the body.These are the 'embryonic stem cells' constituting the 'innercell mass' of the blastocyst (the embryo when it resembles a hollow ball containing amass of stem cells). Stem cells present later in life seem to have less scope fordifferentiation into different cell types but are essential to processes such asdevelopment, growth, blood and tissue renewal, and tissue repair.

Why the interest in stem cells?Understanding stem cells and their differentiation is important to many areas of scienceand medicine. Stem cells are used to develop alternatives to animal testing in toxicologyand drug screening, and are envisaged as targets/vectors for gene therapy.They are seenas a potential source of novel therapies - scientists hope to use them to repair or replaceinjured, dead, or degenerating cells, tissues, and organs. But is this simply a dream or canit become reality?

That stem cells hold promise is clear. Skin grafting and bone marrow transplantation arewell-established procedures that rely on the presence of stem cells in the transplantedtissues. New stem-cell-based therapies are emerging, and ‘proof of principle’ has beenachieved for some of them.Yet not enough is known about stem cells and the signals thatdirect their differentiation.To move from hopeful prospects or even proof-of-principle tolarge-scale standardised therapy will take years of research. It will also take strongcooperation between players in the health care sector, academics, and industry.

What are the possible sources for stem cells?One source for human embryonic stem cell would be to use “spare embryos” – embryosthat are no longer needed for infertility treatment.Another possibility would be to isolateembryonic stem cells from embryos created for research purpose or embryos createdby somatic nuclear transfer (therapeutic cloning).These latter stem cells would have theadvantage of being immunologically compatible with the patient. Foetal stem cells can bederived from aborted foetuses and umbilical cord blood taken at the time of birth. Adultstem cells have been isolated from certain tissues such as bone marrow, skin and bloodused for transplantation. One of the constraints for using adult stem cells has been thedifficulty in isolating the cells and their low potential to differentiate into different celltypes. Nevertheless, recent studies have shown that some adult stem cells may have thesame potential to differentiate as embryonic stem cells, at least in some cases.

Stem cell research in the European Union

IntroductionStem cells and ethicsStem cells raise a number of ethical issues that focus notably on how they areobtained. Sources include early embryos, aborted foetuses, umbilical cord blood, andadult tissues. The most intensely debated issues concern the status of the humanembryo (abortion – obtaining stem cells from the 'spare embryos' left over from invitro fertilisation – creating embryos for research purposes). Other issues includethe patenting and commercial exploitation of human tissues and cell lines, the rightsof patients and cell/tissue donors, the consequences of increased life expectancy inrelation to population policy and global justice.

EU-sponsored stem cell researchUnder the Fifth Framework Programme (Quality of Life), the European Commission(EC) is currently funding 15 stem-cell research projects. They involve 117laboratories and represent a total EC contribution of €27 399 000.The projects fallunder four main headings: neural stem cells, from basic research to clinicalapplication (five projects); stem cells, from differentiation to tissue engineering (fourprojects); haematopoietic stem cells, from bench to bedside (four projects), andethical, legal, and social issues (two complementary projects, one studying the issues,the other looking at the methods used by bioethicists).

The scientific projects are tackling three major fields of potential applications:

� The 'neural stem cells' projects target neurodegenerative diseases for whichthere is no cure, such as multiple sclerosis, Parkinson's,Alzheimer's, etc.;

� The 'tissue engineering' projects illustrate different levels of the 'stem cell'approach, from basic discovery to the development of implants for bone andcartilage repair;

� The 'haematopoiesis' projects look at alternatives to bone marrowtransplantation and new applications for blood-forming stem cells.

The human stem-cell sources used in these projects include cord blood and foetaland adult tissues.And it is important to note that the EC does not fund any researchthat involves creating a human embryo for research purposes alone.

Mesodermal stem cells:from basic biology todevelopment of preclinicalmodels of tissue replacementand cell therapy

Bone marrow transplantation and skin graftingare life-saving procedures based on the tissue-regenerating power of self-renewing (stem) cells.Yet generally speaking, adult mammals have but alimited capacity to regenerate degeneratedtissue, despite the presence of (rare) stem cellscapable of differentiating into a surprisingly widevariety of cell types.The aim of this project is tolearn enough about stem cells to exploit theirexpandability and versatility for therapeuticpurposes. The work involves identifying andcharacterising stem cells in embryonic, foetal, andadult tissues, studying their biology anddifferentiation, and testing their tissue-regenerating capacity in animal models of humandiseases. The project should lead to thedevelopment of protocols for tissue replacementand cell therapy, and has already yielded strikingfindings and material for patents.

Project co-ordinator:

Professor Giulio CossuUniversità di Roma La Sapienza,ItalyDipartimento di Istologia edEmbriologia MedicaPhone: +39 06 4976 6757Fax: +39 06 4462 854E-mail:[email protected]

Partners:

Prof Margaret BuckinghamInstitut Pasteur, Paris, France

Prof Elisabetta DejanaInst. di Richerche Farmacol.Mario Negri, Milano, Italy

Prof Elaine DzierzakErasmus University, Rooterdam,The Netherlands

Dr Fulvio MavilioGenEra s.p.a., Milano, Italy

Prof Terence A. PartridgeRoyal Postgraduate MedicalSchool, London,United Kingdom

Project details:QLK3-1999-00020EU Contribution: €1 435 000Duration: 36 months

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Cord blood as an allogeneicsource of stem cells for clinicaluse

Certain cancers and various disorders of theblood or immune system require treatment thatdepletes the population of stem cells responsiblefor generating the body's blood and immune cells.Bone marrow transplantation is the proceduremost often used to remedy this situation. Thisproject has clearly demonstrated that stem cellscollected from the umbilical cord after a baby isborn can reconstitute a patient's blood-formingsystem as effectively as a bone marrowtransplant. Other advantages of cord bloodtransplantation include easy collection, no dangeror discomfort for the donor, an enormouspotential donor base (the theoretical limit almostequals the number of births), and a lower risk ofgraft-versus-host disease.The work focuses on four main aspects: thecapacity of cord-blood stem cells to reconstitutethe blood-forming system, their immunologicalproperties, their clinical applications, andinterfacing between transplant centres and cord-blood banks.


Professor Eliane GluckmanHôpital Saint-Louis, Paris, FranceBone Marrow Unit Phone: +33 1 4249 9644Fax: +33 1 4249 9634E-mail:[email protected]

Partners:

Prof William ArceseUniversity “La Sapienza”, Roma,ItalyProf Dominique CharronInstitut des Cordeliers, Paris, FranceProf Manuel FernandezUniversity Hospital Clinica Puertade Hierro, Madrid, SpainProf Willem FibbeEurocord Nederland FoundationLeiden University Hospital, Leiden,The NetherlandsProf Joan GarciaInstitut de Recerca Oncologia,Barcelona, SpainProf Alejandro MadrigalAnthony Nolan Bone Marrow TrustThe Royal Free Hospital, London,United KingdomProf Girolamo SirchiaMilano Cord Blood Bank,Milano, ItalyProf Peter WernetBone Marrow Donor CenterHeinrich Heine University,Dueseldorf, GermanyProf Franco LocatelliUnversità di Pavia, Pavia, ItalyDr Bruno PeaultInserm Unité 506,Villejuif, France


Projects

5

Biomechanical interactions intissue engineering and surgicalrepair (BITES)

The BITES project aims to develop biologicalimplants for repairing injured bone and cartilagein load-bearing joints (particularly the knee).Theidea is to create bioartificial organs which consistof load-bearing but biodegradable scaffoldsseeded with cells capable of regenerating thedamaged tissues. The BITES partnership ismultidisciplinary and addresses all aspects of thisnovel tissue engineering strategy: the cells to beused (stem cells from the patient), theirdifferentiation into cartilage- or bone-formingcells, their adhesion to and development withinthe scaffolds, the scaffolds themselves (materials,structure,mechanical properties, biocompatibility,biodegradation, inclusion of signals for celldifferentiation, etc.), and animal models andbioreactors (culture systems) for implant testing.Patent applications will soon be filed for newscaffolds and bioreactors produced during thisstudy, and scaffolds suitable for clinical testing areexpected to be developed by the end of theproject.


Professor Alicia El HajCentre for Science andTechnology in Medicine,United KingdomDepartement of BiomedicalEngineeringPhone: +44 1782 554 253Fax: +44 1782 747 319E-mail: [email protected] Website: http://www.keele.ac.uk/depts/stm/bites/index.htm

Partners:

Prof Charles BaqueyUniversité Victor SegalenBordeaux 2, Bordeaux, France

Prof Adam CurtisUniversity of Glasgow, Glasgow,United Kingdom

Prof Carmelina RuggieroUniversity of Genoa, Genova, Italy

Dr Robert BrownUniversity College London,London, United Kingdom

Dr Patrick PrendergastTrinity College, Dublin, Ireland

Dr Jenneke Klein-NulendACTA-Vrije Universiteit,Amsterdam,The Netherlands

Prof Åke ÖbergLinköping University / UniversityHospital, Linköping, Sweden

Dr John CooperBiocomposites, Stoke-on-Trent,United Kingdom

Dr Andrew RemesRemes Biomedical, Glasgow,United Kingdom

Project details:QLK3-1999-00559EU Contribution: €2 104 999Duration: 36 months6

Lentiviral vectors for genetherapy of the haematopoieticsystem: development frombench to bedside

Gene therapy applied to haematopoietic stemcells (blood-cell-generating stem cells, HSCs) is apromising approach to treating some cancers anda variety of diseases affecting either the blood orthe immune system. For instance, an introducedgene could make a person's immune cellsresistant to the AIDS virus; treated stem cellswould represent a lifelong supply of geneticallymodified immune cells.Yet it is hard to introducea gene into HSCs because they are mostlyquiescent (non-dividing), and existing gene-transfer techniques work best with activelydividing cells.This project focuses on lentiviruses(LV), which show great promise as vectors forintroducing genes into quiescent cells.

In phase I, the project partners will develop genetherapy protocols and reagents, as well asoptimised lentiviral vectors.They will validate LVsafety assays. In phase II, they will conductpreclinical studies in animal models, and in phaseIII they will prepare for clinical trials.The projectmay ultimately lead to treatment for diseasessuch as AIDS, cancer, haemophilia, inheritedimmune deficiencies, and Tay-Sachs disease.


Professor Luigi NaldiniUniversità di Torino, ItalyDepartment of BiomedicalSciences and OncologyPhone: +39 01 1993 3226Fax: +39 01 1993 3225e-mail: [email protected]

Partners:

Dr Didier TronoUniversity of Geneva School ofMedicine, Geneva, Switzerland

Dr Olivier DanosGénéthon III, Evry, France

Dr Claudio BordignonFondazione Centro San Raffaeledel Monte Tabor, Milano, Italy

Dr Alain FischerHopital Necker, Paris, France

Dr Francois-Loic CossetEcole Normale Superieure deLyon, Lyon, France

Dr Fulvio MavilioGenEra S.p.A., Milano, Italy


Projects

7

European cell therapy in thenervous system (ECTINS)

The Ectins project is being co-ordinated by asmall biotechnology enterprise with patents instem cell technology.The aim is to create humanstem cell lines for treating neurological disorderssuch as Alzheimer's, Parkinson's, and Huntington'sdiseases, cerebral palsy, and stroke. The work isbased on the demonstrated ability of mouseneural stem cell lines to repair degeneratingtissue and promote recovery of impairedneurological functions in animal models of braindamage.

The idea is to equip promising cell lines with agene that enables them to grow vigorously andindefinitely in culture (to allow standardisedindustrial production), but that switches off afterthe cells are implanted in a patient's brain (toavoid unruly proliferation). Other objectivesinclude developing assays for predicting theclinical efficacy of candidate cell lines, optimisingdefined media for growing, freezing, and storingthe cells, establishing the clinical potential ofpromising lines in animal models, and developingmagnetic resonance imaging as a non-invasivetool for monitoring the behaviour of the implantsin patients' brains.


Dr John SindenReNeuron Limited, London,United KingdomPhone: +44 1483 30 25 60Fax: +44 1483 53 48 64E-mail:[email protected]

Partners:

Dr Parmjit JatLudwig Institute of CancerResearch, London, UnitedKingdom

Dr Magdalena GoetzMax-Planck Institute ofNeurobiology, Planegg-Martinsried, Germany

Dr Constantine SoteloINSERM, Paris, France

Prof William BlakemoreUniversity of Cambridge,Cambridge, United Kingdom

Prof Charles French-ConstantUniversity of Cambridge,Cambridge, United Kingdom

Dr Finn OkkelsMedi-Cult a/s, Jyllinge, Denmark

Dr Steve WilliamsKings College London, London,United Kingdom

Prof Hannu AronenHelsinki University, Helsinki,Finland

Dr A.VescoviIstituto Nazionale NeurologicoCarlo Besta, Milano, Italy


8

Engineering neural precursorsfor myelin repair

The aim of this project is to produce cells ortherapeutic drugs that will repair the damagecaused by multiple sclerosis (MS) in the centralnervous system (CNS, the brain and spinal cord).MS is due to demyelination, the destruction of the'myelin sheath' that coats certain nerve cells andis essential for the rapid transmission of nervesignals. The sheath consists of cell extensionswrapped around the nerve cell. The projectfocuses on neural stem cells, common precursorsof three types of CNS cells, including thoseforming the myelin sheath. One idea is toengineer these stem cells so that they migratereadily to sites of demyelination and 'choose' torepair the damage. Another is to stimulaterecruitment of a patient's own precursors to thedemyelinated area. Using various animal models,the partners are studying the factors thatpromote precursor migration and 'encourage'neural stem cells to specialise in myelination.Strategies for restoring fast nerve conduction willbe tested in animals with defective myelination ordemyelinating lesions.


Professor Dubois-DalcqInstitut Pasteur, Paris, FranceUnité de Neurovirologie etRégénération du SystèmeNerveuxPhone: +33 1 40 61 34 22Fax: +33 1 40 61 34 21E-mail: [email protected]

Partners:

Geneviève RougonCNRS, Marseille, France

Charles French ConstantUniversity of Cambridge,Cambridge, United Kingdom

Oliver BrüstleUniversity of Bonn, Bonn,Germany

Claudia Pena RossiSerono Pharmaceutical ResearchInstitute, Plan-les-Ouates,Switzerland

Rebecca MatsasHellenic Pasteur Institute,Athens,Greece

Project details:QLG3-2000-30911EU Contribution: €1 409 458Duration: 36 months

Projects

9

Neural stem cells and stem-cell-based therapies

This project aims to provide basic information onstem cell physiology, proliferation, anddifferentiation in order to design cell replacementtherapies for disorders of the central nervoussystem (brain and spinal cord). An importantobjective is to identify the genes whoseexpression determines which cell type(s) a stemcell yields when it divides, and to unravel themechanisms in which these genes participate.Another is to find markers that distinguish thetypes of stem cells that contribute to thedevelopment of the brain and spinal cord, so thatthese can be tracked and modified by mutation.Part of this work is being done in the fruit fly,which is particularly amenable to genetic studies.Then, because vital genes tend to be conserved inthe course of evolution, it is possible to identifycorresponding genes in vertebrates and to studytheir functions. On the basis of the informationgained, cell replacement protocols will bedesigned for testing post-traumatic disorder inanimal models.


Dr Angela GiangrandeCNRS – Délégation Alsace, FranceLaboratoire de GénétiqueMoléculaire des EukaryotesPhone: +33 3 88 65 33 81Fax: +33 3 88 65 32 01E-mail: [email protected]

Partners:

Dr Prof Thomas EdlundUmeea University, Umeea, Sweden

Prof Henrique DomingosFundaçao da Universidade deLisboa, Lisboa, Portugal

Dr Jack Price King's College London, London,United Kingdom

Prof William D. RichardsonUniversity College London,London, United Kingdom

Prof Dr Gerhard M.TechnauJohannes Gutenberg UniversitätMainz, Mainz, Germany

Dr Angelo VescoviFondazione Centro S. Raffaele delMonte Tabor, Milano, Italy


10

Neural stem cells – from basicscience to CNS repair(Neuropair)

Stem cells have the ability both to self-renew andto generate specialised cells.The central nervoussystem (CNS, the brain and spinal cord) ofmammals contains stem cells at all developmentalstages, from embryo to adult. One attractive ideatherefore is to use stem cells for transplantationpurposes, for example to replace degeneratedcells, providing signals so that the stem cells canyield the appropriate cell types. An obstacle todeveloping such therapy is a lack of knowledge onboth neural stem cells and on the signals thatdetermine their behaviour and fate. TheNeuropair project aims to answer questions inthis area, notably by elucidating the functions ofrelevant genes and developing animal models forstem-cell transplantation. In sub-project 1, keygenes have been identified that are important forCNS stem cell maintenance and differentiation.They are being analysed both in cultured cells andby transgenic techniques to see how theycontribute to stem cell fate. In sub-project 2,novel stem cell populations have beencharacterised. Sub-project 3 is based on thefinding that CNS stem cells, in addition togenerating cells typical of the nervous system, canalso yield cell types typical of other tissues. Thisraises the important question of CNS stem-cell'differentiation plasticity' (the range of cell typesobtainable from these cells). Sub-project 4addresses the capacity of various stem cellpopulations and CNS stem cell lines tocontribute to brain function following trans-plantation into rodent brains with lesionsmimicking human diseases. The partners hopethat by approaching stem cell biologysystematically at all these levels, progress will bemade towards the future use of stem cells astherapeutic agents for diseases such asAlzheimer’s and Parkinson’s, of increasingconcern to Europe's ageing population.


Professor Urban LendahlKarolinska Institutet, Stockholm,SwedenDepartment of Cell and MolecularBiologyDepartment of cell and molecularbiologyPhone: +46 8 728 73 23Fax: +46 8 34 81 35E-mail: [email protected]

Partners:

Prof Dr Beat GaehwilerUniversity of Zürich, Zurich,Zwitzerland

Dr Magdalena GoetzMax-Planck-Institute ofNeurobiology, Planegg-Martinsried, Germany

Dr François GuillemotCNRS-Délégation d’Alsace,Illkirch, France

Dr Jack Price King's College London, London,United Kingdom

Dr Angelo VescoviFondazione Centro S. Raffaele delMonte Tabor, Milano, Italy


Projects

11

European network for foetaltransplantation (ENFET)

In utero stem cells transplantation is an alternativeto postnatal bone marrow transplantation, whichis now emerging for genetic disorders of theblood-forming and immune systems that can bediagnosed early in pregnancy. It involvesultrasound-guided injection of stem cells into theabdomen of a 13- to 14-week foetus.Advantagesinclude treatment before any pathologicalsequelae are apparent and the fact that a foetus isimmunologically immature and very receptive tomismatched cells. One-shot treatment ispotentially sufficient and costs less than a bonemarrow transplant. To date about 35 in uterotransplants have been performed worldwide,mostly in Europe. Treatment has provedsuccessful for some but not all disorders. Thereremain important questions to be answered, suchas: what are the indications for foetal trans-plantation? Which stem cells should be used forwhich disorders? The ENFET network aims toexplore the prospects for in utero transplantationby providing a patient database and follow-up oftransplant procedures, deriving protocols forstem cell banking, establishing sources of stemcells, and using data from animal models of inutero transplantation.The consortium will publishguidelines and recommendations for this noveltherapy.


Dr Rhodri JonesUniversity of Nottingham, UnitedKingdomDepartment of Immunology,Queen’s Medical CenterPhone: +44 115 970 9058Fax: +44 115 970 9125E-mail:[email protected]

Partners:

Dr Stephen ParsonsBristol Institute for TransfusionSciences, Bristol, United Kingdom

Dr Fluvio PortaUniversity of Brescia, Brescia, Italy

Dr Sicco ScherjonLeiden University, Leiden,The Netherlands

Prof. Jean-Louis TouraineUniversity Hospital EdouardHerriot, Lyon, France

Dr Wolfgang HolzgreveKantonsspital Basel Universitats-kliniken, Basel, Switzerland

Dr The-Hung BuiKarolinska Institutet, Stockholm,Sweden

Prof. Shimon SlavinHaddassah University Hospital,Jerusalem, Israel

Dr Tsvee LapidotThe Weizmann Institute ofScience, Rehovot, Israel

Project details:QLG1-2000-31475EU Contribution: €344 050Duration: 48 months

12

Chondral and osseous tissueengineering

One aim of this project focusing on bone andcartilage repair is to build tissues outside thebody for transplantation into a lesion. The workinvolves producing biodegradable scaffolds thatcan be seeded with appropriate cell mixtures orpieces of tissue. Biodegradable materials are alsoused to make membranes for guiding tissuegrowth and fixation devices for holding implantsin place. Various tissue-building strategies arebeing tried out, and tissue transfer techniques arebeing developed and tested in animal models.Thepartners will use a wide variety of analytical andimaging techniques to test the quality of thetissues produced and to monitor the healingprocess.At the end of the project, they will applythe most successful methods to patients. Theproject should lead to new treatments forconditions such as degenerative joint disease(osteoarthritis), major craniofacial bone loss, andopen tibial fractures.


Dr Timo WarisOulu University Hospital, FinlandDepartment of SurgeryPhone: +358 83 15 23 16Fax: +358 83 15 24 85E-mail: [email protected]

Partners:

Prof Pertti TormalaTampere University of Technology,Tampere, Finland

Dr Enzio MullerUniversität Tuebingen,Tuebingen,Germany

Prof. Milomir NincovicLeopold-Franzens-UniversitätInnsbruck, Innsbruck,Austria

Dr Eric ArnaudHopital Necker, Paris, France

Prof Peter EbbesenDanish Cancer Research,Arhus,Denmark

Prof Egon ToftMesibo A/S , Copenhagen,Denmark


Projects

13

14

Suicide gene therapy in stemcell transplantation

Graft-versus-host disease (GvHD) is a life-threatening complication associated with stemcell transplantation involving a donor other thanthe patient. It arises when the donor and patientare not well matched for tissue compatibility, andimmune cells from the donor attack the patient'stissues.This project aims to develop a strategy forcuring GvHD: suicide gene therapy.The idea is tointroduce into the donor immune cells a genethat will make them sensitive to a prodrug – aharmless substance that can be converted to anactive drug only by cells possessing the gene.

Phase I of the project will lead to thedevelopment of new suicide genes, selectablemarker genes, and gene therapy vectors, as well aslarge-scale GMP procedures for gene transfer.Phase II will be devoted to preclinical studies inanimal models of transplantation, leukaemia, andGvHD. In phase III, clinical trial protocols will bedeveloped and industrial partners will preparenewly developed vectors and packaging cell linesfor suicide gene delivery in clinical trials.


Dr Maria Chiara BoniniFondazione Centro San Raffaele delMonte Tabor, Milano, ItalyBone Marrow Transplantation Unit andGene Therapy ProgrammePhone: +39 02 26 43 47 90Fax: +39 02 26 43 47 86E-mail: [email protected]

Partners:

Dr Pierre TiberghienFranche-Comté ImmunomolecularTherapeutic Laboratory, Besançon,FranceDr Anton HagenbeekUniversity Medical Center Utrecht(UMCU), Utrecht,The NetherlandsDr Hans-Jochem KolbHämatopoetische Zell-Transplantation,München, GermanyDr Eva WeissingerMedical School Hannover, Hannover,GermanyDr Jane ApperleyImperial College School of Medicine,London, United KingdomDr Paul MossUniversity of Birmingham, Birmingham,United KingdomDr Mark LawlerSt James’s Hospital, Dublin, IrelandDr Sandro MoriMOLMED SpA, Milano, ItalyDr Leonardo ScapozzaETH Zürich, Zürich, SwitzerlandDr Axel R. Zander UkeUniversity Hospital Eppendorf,Hamburg, GermanyDr Hans Georg Eckert EufetsEUFETS GmbH, Idar-Oberstein,GermanyDr M. Sirac Dilber KiHuddinge University Hospital,Huddinge, SwedenDr Els GoulmyLeiden University Medical Center,Leiden,The NerherlandsDr Shimon SlavinHadassah University Hospital,Jerusalem, Israel

Project details:QLK3-2001-01265

EU Contribution: €2 660 400Duration: 36 months

Projects

15

Cellular production of Wnts,secreted growth anddifferentiation factors and theiruse as co-ordinators of organspecific stem cells

The future of stem-cell-based tissue engineeringwill depend on the ability to control – i.e. inhibit,trigger, and direct as needed – stem celldifferentiation.This project focuses on a group ofproteins that might be useful for this purpose:secreted factors called Wnts, known to play a rolein embryonic development. Having shown thatWnts are important stem-cell maintenancefactors in the gut, immune system, and kidney, thepartners aim to develop applications exploitingthe regulatory properties of Wnts. One task is todevelop means of producing Wnt proteins anddetecting Wnts with antibodies produced againstthem.Another is to observe and understand howWnts regulate stem cell behaviour. A third is tostudy the biochemical properties of Wnts and toidentify the receptors to which they bind.Potential applications include, for example, thedevelopment of reagents for diagnostics to detectWnts with their antibodies, and the use of Wntsto maintain stem cells in culture prior to organbuilding/repair.


Professor Seppo VainioUniversity of Oulu, FinlandDepartment of BiochemistryPhone: +358 8 553 11 90Fax: +358 8 553 11 41E-mail: [email protected]

Partners:

Olivier DestreeRoyal Dutch Academy ofSciences, Utrecht,TheNertherlands

Wolfgang LoettelBio Energie Consult GmbH,Halle, Germany

Frédérique RattisGenOway, Lyon, France

Luc LeynsVrije Universiteit Brussel,Brussels, Belgium


16

Development of humandopaminergic neuronal celllines for transplantation(DANCE)

The starting point of this project is a remarkableachievement: successful transplantation of foetalbrain tissue into the brains of patients sufferingfrom Parkinson's disease, with long-term survivalof the grafts and clinical improvement of thepatients. Yet this approach has been taken to itslimit. To carry it further, rather than using foetaltissue, expandable cell lines will be required,which are capable of replacing the brain cellstargeted by the disease (neurons producing theneurotransmitter dopamine). The DANCEproject aims to create such cell lines, with a viewto industrial production and commercialisation.Focusing on stem cells and more immediateprecursors of the target neurons, the workinvolves: (1) identifying, isolating, and culturingsuch cells; (2) propagating them; (3) discoveringhow to make them generate dopamine-producingneurons; and (4) testing them in animal modelsand selecting good candidates. Gene expressionstudies and bioinformatics will support this work.Candidate lines appropriate for clinical trials areexpected within three years.


Dr Lars WahlbergNsGene A/S, DenmarkDepartment of Cell andPreclinical BiologyPhone: +45 4460 8913Fax: +45 4460 8989E-mail: [email protected]

Partners:

Associate Professor AlbertoMartinez SerranoUniversidad Autonoma deMadrid, Madrid, Spain

Associate Professor ErnestArenasKarolinska Institute, Stockholm,Sweden

Professor AndersBjoerklund Wallenberg NeuroscienceCenter, Lund, Sweden

Professor Dr Peter GrussMax-Planck-Institute ofBiophysical Chemistry,Goettingen, Germany


Projects

17

Empirical methods in bioethics

In November 2000, the European Group onEthics expressed the view that it is premature tocreate human embryos by somatic cell nucleartransfer (SCNT: transfer of a tissue cell nucleusinto an egg cell deprived of its nucleus), becauseSCNT is ethically controversial and there existalternative sources of stem cells whosetherapeutic potential has not yet been sufficientlyexplored.

This exemplifies a current trend in bioethics:'empirical bioethics', where knowledge from fieldssuch as biomedicine or sociology is used toestablish ethical standards for life-sciencepractices and applications. The project 'Empiricalmethods in bioethics' aims to assess how thisapproach contributes to concepts of Europeanand universal ethical standards, how it is relevantto public policy concerning health care andbiotechnology, what specific methodologies aremost successful in empirical bioethics, and whatkind of empirical bioethics is most relevant todecisions concerning the regulation of newtechnologies.

The partners will create a database of studiesusing this approach. On the basis of philosophicaldiscussions and case studies (one of which willlook at the use of empirical data in the debate onthe regulation of stem cell research), they will tryto reach a consensus about how to use this kindof knowledge in bioethics and policy-making.Theywill also publish provocative opinion papers onthe subject.


Dr Soren HolmVictoria University ofManchesterInstitute of Medicine, Laws andBioethicsPhone: +44 161 275 70 14Fax: +44 161 275 34 73E-mail: [email protected]

Partners:

Dr Isabelle Baszanger CERMES - Centre de recherchemédecine, sciences, santé etsociété (CNRS - INSERM)

Prof Heta Aleksandra GyllingUniversity of Helsinki

Mr Peter RosselUniversity of Copenhagen

Prof Jan Helge SolbakkUniversity of Oslo

Dr Maurizio MoriUniversita Degli Studi DiMilano-Bicocca

Dr Carlo Alberto DefantiOspedale Niguarda Ca’ Grande

Dr Mairi LevittUniversity of Central Lancashire

Prof Amos ShapiraUniversity of Tel Aviv

Docent Peter OhrstromAlborg Universitet


The ethics of human stem cellresearch and therapy in Europe(Eurostem)

The Eurostem project aims to create an ethicalframework for human stem cell research andtherapy. Legal experts, theologians, philosophers,and a representative of industry are tacklingissues such as the moral status of the humanembryo, the rights of patients and cell/tissuedonors, the ownership of human tissues, cell lines,and genetic information. Information is gatheredfrom many sources (legal documents, conventionsand treaties, research protocols, surveys, thepress and media) and analysed with the tools ofdiverse disciplines, from law and sociology tomoral philosophy.

Care has been taken to bring together teamsrepresenting a wide range of religious andphilosophical approaches. The partners do notexpect to reach a consensus on all points, buthope to identify areas where an accord ispossible. Liaising with actors and stakeholders inmany sectors of society, they will elaborateethics-based principles and guidelines for stemcell research and therapy.


Professor John HarrisUniversity of Manchester, UnitedKingdomInstitue of Medicine, Law andBioethicsPhone:+44 161 275 34 14Fax: +44 161 275 34 73E-mail: [email protected]

Partners:

Prof Dr Carlos Romeo-CasabonaUniversidades Deusto / Pais Vasco,Bilbao, Spain

Prof Inez De BeaufortErasmus University Rotterdam,Rotterdam,The Netherlands

Prof Stefano RodotaFondazione Ielio e Lisli Basso,Roma, Italy

Prof Goran HermerenLund University, Lund, Sweden

Prof Dr Ludger HonnefelderInstitut für Wissenschaft und Ethike.V., Bonn, Germany

Prof Ruth ChadwickLancaster University, Lancaster,United Kingdom

Dr Andrew DearingEuropean Industrial ResearchManagement Association, Paris,France

Project details:QLG6-2001-00072EU Contribution: €747 000Duration: 36 months

18

� Osteochondral construct -Biodegradable scafold seededwith human stem cellsdifferentiated into cartilage cells(top layer) and bone cells(stained purple in lower layer).Kindly provided by P. El Haj.

� Fluorescence immunocyto-chemistry of human hetero-geneous primary fetal brainstem cell preparation showingthat a proportion of the cells(cell nucleus stained blue) arestem cells, showing the charac-teristic filamentous expressionof the neural stem cell marker,nestin (in green)Kindly provided by J. Sinden.

� Triple labelling images of'epigenetic' neural stem cellsgrown in aggregate culture. Blueis cell nucleus, geen is nestin(neural stem cell marker), red isGFAP, a marker of astroglia butalso expressed in some neuralstem cells. Combination imagesbottom panels. Note cellularmigration away from theaggregate.Kindly provided by J. Sinden.

� High power image at edge ofaggregate culture showingmigration away from theaggregates. Blue is cell nucleus,green is nestin (neural stem cellmarker), red is GFAP, a markerof astroglia but also expressedin some neural stem cells.Combination images bottompanels.Kindly provided by J. Sinden.

Projects

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Source of the images: ReNeuron Ltd

For further information visit The Stem cells website on the Europa server:

http://europa.eu.int/comm/research/quality-of-life/stemcells.html

The Stem cells discussion platform was the starting point for a dialogue in which anyone concernedby the importance of the changes being brought about by progress in the life sciences is welcome to

take part. Ideas, proposals for action and other initiatives should be sent to:

[email protected]

Documents

Stem Cells - Therapies for the future? - Projects catalogue; haematopoietic stem ... from basic biology to development of preclinical ... graft-versus-host disease. The work focuses