The approach taken was that of systems biology combining experimental work with computational modelling. In this way, the two equal-first authors of the paper were able to iterate between the empirical and the theoretical: the lab-work of Jelena Raspopovic providing experimental data for the model, and the computer simulations of Luciano Marcon making predictions to be tested back in the lab.
By screening for the expression of many different genes, they found that two signalling pathways stood out as having the required activity patterns: BMPs and WNTs. They gradually constructed the minimal possible mathematical model compatible with all the data, and found that the two signalling pathways were linked through a non-diffusible molecule the transcription factor Sox9. Finally, they were able to make computational predictions about the effects of inhibiting these 2 pathways either individually, or in combination which predicted how the pattern of fingers should change. Strikingly, when the same experiments were done on small pieces of limb bud tissue cultured in a petri dish the same alterations in embryonic finger pattern were observed, confirming the computational prediction.
This result answers a long-standing question in the field, but it has consequences that go beyond the development of fingers. It addresses a more general debate about how the millions of cells in our bodies are able to dynamically arrange themselves into the correct 3D structures, for example in our kidneys, hearts and other organs. It challenges the dominance of an important traditional idea called positional information, proposed by Lewis Wolpert which states that cells know what to do because they all receive information about their "coordinates" in s
|Contact: Juan Manuel Sarasua|
Center for Genomic Regulation