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Introduction

Recent findings in Developmental Biology concerning the signaling pathways that lead to the production of many different cell types during embryonic stages of life are vital to, and advance our knowledge of, the normal processes involved in tissue maintenance and cell replacement during adult life. Such signaling pathways are the basis of the "turning on and off" of specific panels of genes. These genes are controlled by a limited number of regulatory genes that react to the signals, thereby setting up a "molecular memory" to the cell and giving it a specific identity. In the context of multifactorial disease, trauma and the environment, innovative genetic and biochemical approaches in Developmental and Stem Cell Biology offer great potential for clinical intervention in the form of novel molecular and cellular therapies.

This innovative knowledge biomedical technology research program concerns Stem Cells in Development and Disease and aims to identify and characterize the genetic cascades and regulatory pathways that control cell identity throughout development in several stem cell and tissue systems. To achieve these goals, we will utilize integrated biochemical and functional genetic approaches, combining gene expression analysis, novel gene disruption technology, stem cell culture systems and rapid monoclonal antibody production. Bioinformatics databases will be integrated using the latest three dimensional visualization technology and will lead to a new perception of multifactorial processes. This in turn will lead to validation and the subsequent formulation of novel intervention strategies for disease and trauma.

The knowledge program, Stem Cells in Development and Disease, integrates the knowledge infrastructure of 11 internationally competitive Dutch research laboratories specializing in developmental, stem cell and molecular biology, together with 4 biotechnology companies, to advance biomedical technology and applications in human health and disease.

The recent high interest in cell replacement therapies for multifactorial diseases, trauma and environmental circumstances relies to a large extent on insights coming out of the field of Developmental Biology. Just last summer, a group of Developmental Biologists discovered the complete series of inductive signals and transcription factors necessary to recapitulate the normal generation of motor neurons (a finding of great interest to spinal cord injury patients). These fully functional motor neurons were generated from embryonic stem (ES) cells, the most primitive culturable source of cells for all cell lineages. Thus, inductive signals and transcription factors involved in the normal developmental pathways during embryogenesis can be used in the future to direct ES cells or other somatic cells to form specific classes of cells to be used in vivo.

The Netherlands has been on the forefront of Developmental Biology, beginning with the findings of Nieuwkoop and most recently, with important contributions in the understanding of signaling pathways. For example, the groups of Clevers (Utrecht) and Fodde (Leiden) have shown that the Wnt developmental signaling pathway affects the differentiation of gut stem cells and thus is implicated in intestinal-related disease and tumorigenesis. Using such developmental strategies, the outcome of these findings and the many other findings of the Dutch Developmental Biology community most certainly will lead to future clinical therapeutic applications for developmental defects, trauma and tumorigenesis. From the earliest stages of embryogenesis, and particularly during the stages of cell fate determination, organogenesis and homeostasis/normal cell replacement, defective developmental processes result in a wide range of syndromes and diseases. These include for example thalassemia, sickle cell anemia, and particularly childhood leukemias in the hematopoietic system; haemorrhagic telangiectasia in the circulatory system; multiple sclerosis and Charcot Marie Tooth disease in the nervous system; hypospadias and infertility syndromes in the genital and gonadal system; craniofacial malformations and congenital malformations of limbs. By understanding the genetic programs and signaling pathways leading to normal development, we will be better able to control the environmental and genetic factors that lead to infertility, abnormal fetal growth and defective formation and functioning of complex organ systems. The basis of development is within the genes. Indeed, the genetic program leading to production of all the different cell types to form an embryo and ultimately the adult, begins shortly after fertilization. As the fertilized egg begins to divide, the complex regulation of gene expression results in changes within the exponentially increasing number of embryonic cells and in their interactions with each other, leading to the specification of cells for all the organ systems. The understanding of genetic programs and the cell-cell interactions that influence these programs particularly in stem cells, is by no means complete. New genes and signaling pathways have yet to be identified. Complete signaling pathways in cell fate determination and differentiation need to be elucidated. Underlying principles controlling stem cell growth and differentiation are yet to be uncovered. Novel genetic and biochemical approaches offer enormous opportunities to extend our knowledge of normal development and stem cell biology, through not only the identification and classification of key regulatory molecules and signaling cascades, but also through functional testing regimes. Ultimately, these findings should lead to advances in disease treatments through cell replacement therapies and molecular intervention. The aims of this knowledge biomedical technology research project, Stem Cells in Development and Disease, are to identify and characterize the signaling cascades and regulatory pathways that control stem cell differentiation throughout development. This will be achieved through integrated functional genetic approaches and databases, combining a novel gene targeting ES cell strategy, Cre-lox technology, 3D optical microscopy and tomography on embryos and tissues, gene and protein expression analysis, stem cell cultures and rapid single chain monoclonal antibody generation. The eludication and understanding of developmental signaling and regulatory processes will be of great relevance for future therapeutic intervention both at the molecular and cellular levels.

To achieve these ambitious aims in innovative knowledge research for multifactorial and environmentally influenced genetic disease, we have formed a comprehensive working group of prominent and successful developmental, stem cell and molecular scientists within the Netherlands. This Developmental Biology and Stem Cell initiative brings together a unique combination of 11 top-level academic researchers within 4 major Dutch universities/research institutes and several Biotechnology Companies (Dutch and foreign) that will make it possible to carry out this enterprising research program.

Some interactions between these prominent research groups already exist. Within the MGC Research School, there are established research and teaching links between Erasmus, Leiden and Utrecht University Groups (E. Dzierzak, F. Grosveld, D. Meijer, A. Grootegoed, P. Verrijzer). Several of these groups also collaborate within the Centre for Biomedical Genetics (CBG: H. Clevers, F. Grosveld, P. Verrijzer). A few scientific collaborations already exist including those between J. Deschamps (Hubrecht) and M. van Lohuizen (NKI); M. van Lohuizen (NKI), F. Grosveld (Rotterdam) and P. Verrijzer (Leiden); H. Clevers (Utrecht) and R. Fodde (Rotterdam); P. Verrijzer (Leiden) and R. Fodde (Rotterdam). Interactions between academic groups and industry include: H. Clevers and R. Fodde; ESI (Singapore) and C. Mummery; Minos Biosystems (UK) and F. Grosveld. However, through the realization of our innovative Knowledge Research Project in biomedical technology, a larger, highly advantageous and more integrated/interactive program will be achieved. Previously this has not been possible due to the lack of an appropriate subsidy scheme. While the European Community offers subsidy opportunities for integrated research programs between many European laboratories, the Bsik knowledge program for the first time offers the opportunity to form a cohesive and structured research program between the many expert Developmental, Stem Cell and Molecular Biology laboratories existing entirely within the Netherlands. We expect the program to grow by either incorporating new expertise or topics in the form of "young talent" (10% of budget, see below).