Have you ever asked yourself ‘Why is my heart on the left and my liver on the right?’

Heart to the left. Liver to the right. That’s where you’ll find these organs in a healthy human body, but surprisingly, in some people, the heart is on the right and the liver on the left. This normal or abnormal asymmetry can be traced back to your embryonic stage. In the early days of your development, a small fluid-filled cavity known as an embryonic node formed on your embryo. Inside, tiny micro-hairs known as cilia create a flow pattern that steers where organs grow in your body. However, the science behind this flow process has remained a mystery until now. Researchers from Eindhoven University of Technology and the University of Groningen have revealed key details behind the process by building a world-first artificial embryonic node – using synthetic magnetically-controlled cilia to generate a flow pattern – and then explore what happens in the node using advanced simulations. They published their findings on March 25 in the scientific journal Science Advances.

Embryonic origins

“It can be traced all the way back to your first period as an embryo,” says Jaap den Toonder, full professor in the Department of Mechanical Engineering and chair of the Microsystems section at TU/e. “And it has to do with what happens in something called an embryonic node.”

An embryonic node is a small cavity that contains a fluid (made up of water, proteins, hormones, and other substances). The top is closed off by a membrane, while the bottom layer is lined with a few hundred tiny micro-hairs called cilia. The whole node is just a few hundred micrometers across. “The cilia in the embryonic node rotate in the same direction, making a tilted conical motion. This generates an anticlockwise fluid flow inside the node, and it’s this flow that is known to play a key role in the left-right symmetry,” notes Den Toonder.

An artificial node                      

“A critical question that remains unanswered though is how exactly the flow instigates the left-right distribution of organs in the body. Previous studies hinted at various reasons – such as how the cilia move and chemical processes – playing a role, but no studies have uncovered how it works precisely,” says Den Toonder.

To answer this question, Den Toonder led a project to design a world first – an artificial embryonic node. Developing the artificial embryonic node were Tanveer ul Islam, Yves Bellouard (associate professor at EPFL, Switzerland), and Den Toonder, while Ishu Aggarwal and Patrick Onck (both at the University of Groningen) led efforts to develop a model to simulate the embryonic node.

Treating cilia as rigid rods

To date, no groups have been able to simulate the complete embryonic node as current models require vast computational power and resources. “To simulate the fluid flow in the embryonic node, the cilia were modeled as rigid rods that exactly follow the time-varying magnetic field from the experiments. By placing the cilia at the measured positions, we were able to accurately simulate the cilia-induced flow pattern from the experiments.”

The researchers at Groningen used their own in-house algorithm to simplify the simulation of fluid flow in the embryonic node. “Many algorithms discretize the fluid into a mesh with very small elements, but in three dimensions it gets harder to solve the system – especially for an embryonic node at the micrometer scale that consists of over hundreds of cilia. Instead, we created a set of equations to approximate the fluid and remain solvable in a feasible amount of computational time. Despite this, the simulations still took months of computer time on our high-performance supercomputing facilities of the University of Groningen,” adds Patrick Onck.

“The main thing to note is that we captured the induced flow together with the convection and diffusion of morphogens within the fluid in the embryonic node as well as the small-scale deformation of the primary cilia. In combination with the experiments, these combined approaches were essential for us to show what breaks the left-right symmetry, namely the combination of the two synergetic mechanisms.”