The research group of Jacco van Rheenen, working with the group of Benjamin Simons from Cambridge, have discovered a simple but unifying model to predict the formation of complex branched structures of multiple organs. This model, which consists of only three simple rules, surprisingly shows that a gradient of growth factors is not essential to coordinate the development and shape of branched organs. The results are published in Cell on September 21.

Branched networks of ducts
To sustain life of complex multicellular organisms, it is essential to exchange gases and fluids with the environment. To do this in an efficient way, larger organisms, such as mammals, developed several strategies to maximise the area through which organs can exchange nutrients and waste products. One way to enlarge the exchange surface is by the formation of branched structures. This strategy is used by organs such as the lungs, kidneys, prostate, pancreas, the circulatory system, and the mammary gland. These organs all consist of ducts in a branched tree-like structure.

Branch and elongate
Previous research by aforementioned research groups, published earlier this year in Nature (link to article), already showed that the branched ducts of the mammary gland and kidney are formed by multiple cycli of branching and elongation of the ductal tips. However, the timing of the branching is a stochastic process. This leads to a large variety of branching patterns, and the branching pattern does not seem to be determined beforehand.

Large amounts of data
To understand this, the authors collected a large amount of quantitative data on the branching patterns of the murine mammary gland and kidney, and the human prostate. Based on these data they developed a computer model that accurately predicts the structure and size of all the branching patterns found in these organs, based on a few generic rules.

Computer model for branched organs
The model that accurately predicts the structure of branched organs turned out to be a surprisingly simple model and was inspired by the theory of BARWs (branching and annihilating random walks). This unifying model consists of three simple rules: 1. ductal tips elongate with a fixed rate in any direction; 2. at any moment in time a ductal tip can branch with a constant branching probability; 3. a ductal tip will terminate when it comes in close proximity to a neighbouring duct.

Unexpected conclusion
Previously, it was thought that a growth factor gradient would be essential for the growth and development of branched organs. An unexpected conclusion from the new model of branching morphogenesis is that such a gradient is not required; the three unifying rules are sufficient to accurately predict the developmental dynamics of these organs.

Disease development
The developed model not only explains the dynamics of organ development, but also provides us with new insights in how these rules are dysregulated during disease development. In the future, this will help us to better understand the development of diseases such as cancer.

Prof. dr. Jacco van Rheenen is a group leader at the Hubrecht Institute (KNAW) and professor of Intravital Microscopy at the University Medical Center Utrecht.

A unifying theory of branching morphogenesis
Cell 2017