The goal of SIMBIONT is to build the first full computer simulation of mammalian organogenesis – in this case limb development. Understanding the genes, signalling pathways and molecular networks that underlie organogenesis has enormous potential impact, both scientifically and medically.
Scientifically, it is a prime biological example of complex multi-scale control – in which macroscopic and microscopic phenomena feedback to control each other. In particular, the macroscopic state of the system (at the organ scale) feeds back to control at least two types of microscopic cellular decisions: Firstly, during development cells constantly make choices about which cell type to adopt (for example bone cells versus muscle cells). Secondly, cells also continually make choices about which physical movements to make – to migrate, contract, divide or die.
At the heart of these decisions are many hundreds of genes and proteins wired together into cellular networks (or “control circuits”). The dynamically changing states of these cellular networks reflect the decisions being made, but this process cannot be understood by molecular analysis alone. As a cell’s position changes during morphogenesis, the range of signals it receives from neighbours also changes, simply as a consequence of these geometric rearrangements. Thus, genes control cells, but cell movements equally control genes, creating a multi-scale feedback loop. Such complex feedback systems can display very non-intuitive behaviour, and we are therefore still far from understanding how organs are reliably constructed. To do so will require integrating many types of data and sophisticated computer modelling, and thus represents a scientific grand challenge.
Medically, developmental genes and networks are central to: (a) human congenital abnormalities – such as heart defects or polydactyly (which affects 1 in 500 births), (b) cancer - many pathways of interest for tumor control have been discovered as examples of de-regulated development, (c) stem cells - the process of organogenesis is essentially the control of large populations of mulitpotent progenitor cells, and most excitingly (d) regenerative medicine - these pathways clearly underlie the promise of tissue and organ regeneration.
The organ chosen for the SIMBIONT project is the developing limb, because it is the most tractable example of mammalian organogenesis. It was already studied intensively by embryologists in the 1940s and 50s, long before molecular biology entered the field, which encouraged the development of strong conceptual frameworks regarding “organisers” – regions of tissue which secrete diffusible signals to coordinate growth and patterning. Studies of limb development have thus contributed some of the key principles to the field, which remain invaluable today. Since the 1980’s this conceptual framework has been complemented by a wealth of molecular data, and experimental genetics from the mouse. Over 1,800 mutant mouse strains have been documented with defects in limb develoment, and the ability to generate sophisticated genotypes now means that double or even triple limb-specific conditional knock-outs have become increasingly common within the field. Finally, it is clear that both the principles of multi-scale coordination and the specific genes involved will be very relevant to many other organ systems.
