Article

Our nerve cells face an extraordinary logistical challenge: they have to deliver essential materials through extremely narrow spaces, along tiny tracks, over distances up to one meter. When this internal delivery system breaks down, nerve cells can be damaged, giving rise to serious neurological diseases. In a new project, researchers from Dresden, Warwick, and Göttingen want to uncover the rules that keep this microscopic traffic flowing. The European Research Council (ERC) is funding the project with a Synergy Grant of 10 million euros, around 3.5 million of which will go to Stefan Diez, professor at the B CUBE – Center for Molecular Bioengineering at TUD Dresden University of Technology and Max Planck Fellow at the Max Planck Institute of Molecular Cell Biology and Genetics.

Our cells are busy places. At any moment, countless packages are on the move through a complex delivery network: some carry signaling molecules, others carry tiny powerhouses. Molecular motors act as delivery vehicles, hauling these packages along microscopic tracks. The deliveries have to reach different destinations, travel at different speeds, and often squeeze through spaces barely wider than the packages themselves.

In nerve cells, there is an additional challenge of scale. A single molecular motor travels along tracks that are only fractions of a millimeter long, yet the complete transport system must reliably deliver packages over distances up to one meter, for example from the spinal cord to the toes.

When Transport Fails

If this delivery system breaks down, the longest nerve cells are often the first to suffer. Defects in intracellular transport have been linked to several inherited neurological diseases, including Charcot-Marie-Tooth disease, hereditary spastic paraplegia, and spinal muscular atrophy. These diseases damage the nerves that control movement and sensation, leading to muscle weakness, stiffness, or loss of feeling, often in the legs and feet first.

“Surprisingly, we don’t really understand how this traffic stays organized, and without that, we cannot really address what goes wrong in these diseases. In a way, we are now setting out to discover traffic rules inside our cells,” explains Stefan Diez, research group leader at the B CUBE, principal investigator at the Cluster of Excellence Physics of Life (PoL), and Max Planck Fellow at the Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG).

Three Approaches to One Problem

Researchers want to find out how packages pass each other, how the vehicles get around obstacles and switch tracks, and how the transport can continue over very long distances without major traffic jams.

To do this, the ERC Synergy project “TransportRules” brings together three groups with complementary expertise: Stefan Diez in Dresden, Anne Straube at the University of Warwick, and Stefan Klumpp at the University of Göttingen.

In Warwick, the team will observe how packages move in living human nerve cells. In Dresden, they will rebuild the entire transport system in the laboratory. In Göttingen, computer simulations will show how all the parts work together.

“Inside nerve cells, cargo travels along complex networks of tracks, often moving in opposite directions and at very different speeds. Yet somehow, cells manage to avoid constant traffic jams,” explains Anne Straube.

“Understanding how traffic inside the nerve cells works requires us to combine our different perspectives. Only through close collaboration can we answer questions that none of the three groups could tackle alone,” adds Stefan Klumpp.

Recreating Traffic Systems in a Petri Dish

The Diez group in Dresden specializes in the biophysics of motor proteins. The team combines advanced microscopy techniques with precise engineering of microscopic structures and experiments with biological molecular motors. For the new project, they will build a synthetic transport system that reproduces the physical challenges found inside nerve cells as closely as possible.

“We will design networks of extremely thin tracks, similar to those used for transport in nerve cells, and build artificial, adjustable packages to test how different types of cargo move along these tracks,” explains Stefan Diez. “This will also allow us to study traffic jams and collisions.”

The project will run for six years, creating opportunities for young scientists to work across disciplines and spend time in partner laboratories in Germany and the UK.

“Together, we hope to develop a quantitative model of the traffic system that explains the rules behind the normal transport and why it is so robust. This would give us the understanding we need to explain how traffic breaks down in disease, and a basis for developing new therapeutic strategies,” says Stefan Diez.

Transport in an axon where kinesin motors (orange) pull cargos towards the axon tip while dynein motors (red) bring cargoes to the cell center. Copyright: Stefan Diez, generated with ChatGPT6, based on schematic drawings by Anne Straube.