How do our organs know when to stop growing? A multidisciplinary team led by researchers from UNIGE and MPIPKS has solved the mystery of how an organ changes size depending on the size of the animal using a mathematical equation. – ScienceDaily

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The smallest fish in the world, the Paedocypris, measures only 7 millimeters. It is nothing compared to the 30 feet of the whale shark. The tiny fish shares many of the same genes and anatomy as the shark, but the dorsal and caudal fins, gills, stomach and heart are thousands of times smaller! How do the organs and tissues of this miniature fish stop growing very quickly, unlike those of their giant cousin? A multidisciplinary team led by scientists from the University of Geneva (UNIGE), Switzerland, and the Max Planck Institute for the Physics of Complex Systems (MPIPKS), Germany, was able to answer this fundamental question by studying its physics and using mathematical equations, as revealed by their work published in the journal Nature.

The cells of a developing tissue proliferate and organize themselves under the action of signaling molecules, the morphogens. But how do they know what size is suitable for the living organism to which they belong? The research groups of Marcos Gonzalez-Gaitan, professor at the Department of Biochemistry at the Faculty of Sciences at UNIGE and Frank Jülicher director at MPIPKS in Dresden, have solved this mystery by tracking a specific morphogen in cells of tissues of different sizes in the fruit fly Drosophila.

In Drosophila, the Decapentaplegic morphogen (DPP), a molecule necessary for the formation of the fifteen appendages (deca-penta) (wings, antennae, mandibles, etc.) diffuses from a source located within the developing tissue and forms then decreasing concentration gradients (or gradual variations) as it moves away from the source. In previous studies, the group of Marcos Gonzalez-Gaitan, in collaboration with the German team, showed that these gradients of concentration of DPP extend over a larger or smaller area depending on the size of the developing tissue. Thus, the smaller a tissue, the lower the propagation of the DPP gradient from its scattering source. On the other hand, the larger a tissue, the greater the propagation of the DPP morphogen gradient. However, the question remained as to how this concentration gradient adapts to the increasing size of the future tissue / organ.

A multidisciplinary approach to solve a biological question

“The original approach of my team, made up of biologists, biochemists, mathematicians and physicists, is to analyze what is happening at the level of each cell, rather than placing our observations at the level of the tissue”, comments Marcos Gonzalez -Gaitan. “The central point is to treat living matter as if it were only matter, that is to say to study biology with the principles of physics”, explains Frank Jülicher. The two teams have developed a battery of sophisticated tools to follow the fate of the DPP molecule in and between cells of a tissue with great precision using quantitative microscopy techniques. “These tools have enabled us to define a multitude of parameters, linked to cellular processes, for this morphogen. For example, we measured how efficiently it attaches to cells, penetrates inside cells, breaks down or is recycled by the cell before diffusing back to other cells. In summary, we measured all the important transport steps of DPP, ”explains Maria Romanova Michailidi, senior researcher in the Department of Biochemistry and first author of this study.

The scaling mechanism explained by a mathematical equation

Scientists collected all this data on DPP in cells belonging to tissues of different sizes in normal flies and in mutants that could not evolve. They found that it is these different individual transport steps that define the extent of the gradient. Thus, in a small tissue, the DPP molecule spreads mainly by diffusion between cells. Its concentration therefore drops quite rapidly around its source due to degradation, giving a narrow gradient. On the other hand, in larger tissues, the DPP molecules that have entered the interior of the cells are also highly recycled, which allows the gradient to be extended over a larger area. “We were finally able to come up with a unified and unbiased theory of morphogen transport, going right down to the key system equations and unraveling the scaling mechanism!” Maria Romanova is enthusiastic.

The combination of theoretical physics and experimental approaches, established from the study of the DPP molecule in Drosophila, can be generalized to other molecules involved in the formation of various developing tissues. “Our unique and multidisciplinary approach allows us to provide a universal answer to a fundamental biological question that Aristotle was asking himself almost 2,500 years ago: how does an egg know when to stop growing and make a hen? concludes Marcos Gonzalez-Gaitan.

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