A strong emphasis of genomics, bioinformatics and computational biology is at the molecular scale, however many of the things we wish to understand occur at the macroscopic scale of organs and organisms. At the molecular scale, regulation of genes and proteins creates complex networks which control cell activities (division, migration, cell fate decisions, differentiation, and many others), with both an intracellular part (circuits of transcription factors) and an extracellular part (secreted ligands, etc). The coordination of thousands of cells by this extended molecular network, leads to large-scale morphogenesis at the scale of tissues and organs. However, these large-scale tissue movements also feedback to the molecular scale: the movement of tissue regions relative to each other causes cells to receive dynamically changing concentrations of signaling molecules, and this in turn changes the activation or repression of genes and proteins. A full understanding of this large-scale feedback between genes, cells and tissues will require multi-scale computer modeling, and we have chosen vertebrate limb development as a model system to explore this problem. Crucially, the data on gene expression and tissue movements should be both dynamic and spatial. Traditional high-throughput “omics” technologies do not preserve spatial information, and we therefore develop novel 3D imaging technologies (OPT and SPIM) to generate geometric and spatial data for the models. I will present results of this interdisciplinary modeling approach, which is gradually allowing us to tackle this complex problem.
James Sharpe was originally captivated by computer programming, but upon learning about the digital nature of the genetic code, chose to study Biology for his undergraduate degree at Oxford University (1988-1991). He then did his PhD on the genetic control of embryo development at NIMR, London (1992-1997) and in parallel started writing computer simulations of multicellular development. During his post-doc in Edinburgh, he began modelling the dynamics of limb development, and due to the lack of 3D data available invented a new optical imaging technology called Optical Projection Tomography (OPT), which is dedicated to imaging specimens too large for microscopy - tissues and organs. In 2006 he moved to Barcelona, becoming a senior group leader at the Centre for Genomic Regulation, and focusing on a systems biology approach to modelling limb development – combining experimentation with computer modelling. In this way the group demonstrated that the signalling proteins which pattern the fingers during embryogenesis, act as a Turing reaction-diffusion system. In 2011 he became the coordinator of the Systems Biology Program, and in 2017 was recruited to EMBL as Head of the new Barcelona outstation on Tissue Biology and Disease Modelling.