PRESS RELEASE
NEW SUCESS FOR COMPUTATIONAL BIOLOGY: RESEARCHERS FROM THE CRG PROVIDE NEW DISCOVERIES ABOUT LIMB DEVELOPMENT 

A team from the Systems Analysis of Development laboratory of the Centre for Genomic Regulation has provided new data about the development of arms and legs during embryonic development.

The work, published in the journal PLOS Biology, presents the first three-dimensional replica of the growth of an embrionic leg which allows a realistic simulation of its development. Thanks to this computer model, the investigators have been able to question current theories explaining limb development and they have thus predicted new factors which must be taken into account.

The study of limb development in vertebrates has often been used as a model system for spatial control in cell formation. At the beginning of their development, arms and legs are basically protuberances of undifferentiated cells with no determined function. As development advances, from several hours to serveral days depending on the species, these cells mature until they become specific types of cell, for example, bone, muscle, nerve or blood cells. At the same time, the cells divide and move collectively, changing the size and shape of this protuberance until the extremity is fully developed. Part of this transformation is the elongation of the limb along the proximodistal axis, which was the object of study of the researchers from the Centre for Genomic Regulation (CRG).
Classical experiments try to explain extremity development based on the observation of the number of cell divisions and cellular density throughout the extremity during its development. The most accepted hypotheses support the existence of a cellular proliferation gradient over which the distal cells (those furthest from the body) divide faster than the others, provoking the elongation of the extremity. In other words, the theory proposes that the cells must know where they are (further or closer from the body) but they do not have to know which direction they are pointing. 

Researchers from the Systems Analysis of Development laboratory of the Centre for Genomic Regulation have studied the limb development from a new computational angle, which has allowed them to identify new important factors necessary for correct development. Specifically, the group lead by James Sharpe has, for the first time, obtained quantitative and comprehensive data about cellular proliferation and density. Instead of a traditional description, the data set is composed of numeric values collected for the whole organ, enabling the construction of a three-dimensional computer model of the development of the extremity. 

Thanks to this dynamical computer model, the researchers have observed the existence of new factors to take into account to explain limb morphogenesis. Although previous work suggested that the individual behaviour of the cells did not have to be directional and explained the elongation of the extremities by a cellular proliferation gradient (the distance of each cell to the body determining the speed of division), the work of Sharpe and his collaborators reveals that these proposed non-directional factors are insufficient to explain the resulting elongation. “We have observed that in order to develop properly, the cells must point in carefully controlled directions” explains Bernd Boehm, the first author of the work.

“Our project has revealed new important factors for extremity development which until now have not been taken into account” affirms the ICREA research professor and chief of the Systems Analysis of Development group of the CRG, James Sharpe. “Experimental data are no longer sufficient and computer models and simulations are here to stay”, he adds. “New microscopic technology and optical projection together with computational analysis of experimental data allow us to create useful models to study processes in much more depth” concludes Sharpe. 

Biological research is becoming more and more multidisciplinary and this study is a good example. The work of James Sharpe and his team proposes a model to explain the cellular processes which take place during limb development and which are common to the development of other organs, so the data obtained can be extrapolated to these too. To enable this, within the Systems Analysis of Development lab biologists, computer scientists, physicists and even engineers work together. 

Reference work: Boehm B., Westeberg H., Lesnicar-Pucko G., Raja S., Rautschka M., Cotterell J., Swoger J. & Sharpe J. (14th July 2010). “The Role of Spatially Controlled Cell Proliferation in Limb Bud Morphogenesis” PLOS Biology 8(7):e1000420. DOI: 10.1371/journal.pbio.10000420.