Combining expertise in organoids and sequencing technologies for ALS research

MDC researchers received a $150,000 pilot project grant from the Chan Zuckerberg Initiative's Neurodegeneration Challenge Network to investigate a defining feature of amyotrophic lateral sclerosis (ALS).

By combining expertise in neuromuscular organoids and the latest sequencing technologies, researchers at the Max Delbrueck Center for Molecular Medicine in the Helmholtz Association (MDC) aim to clarify how mutations in RNA-binding proteins cause motor neurons to die in ALS patients. This joint endeavor is taking off thanks to the Chan Zuckerberg Initiative (CZI), which awarded Dr. Mina Gouti and Professor Nikolaus Rajewsky a Collaborative Pairs Pilot Project Award, a grant for new, interdisciplinary collaborations. Together, they plan to get a detailed picture of how mutations affect RNA processing and how this influences the progression of ALS.

We will be able to see where the disease starts, which population of cells is affected first - is it in the motor neurons first, or the skeletal muscle?"

Dr. Mina, Head of Stem Cell Modeling of Development and Disease Lab

No time to waste

ALS is an incurable, fast-moving and complex disease. As motor neurons die, connections with the skeletal muscle deteriorate. As the disease progresses, patients lose muscle coordination, the ability to move their limbs, and ultimately, to breathe. Several genetic mutations are associated with ALS, but the precise steps leading to motor neuron death is unknown. Understanding the process could help identify potential interventions or treatment targets.

"If motor neurons die, you cannot do anything to get them back," says Rajewsky, who heads the Systems Biology of Gene Regulatory Elements Lab and is Scientific Director of MDC's Berlin Institute for Medical Systems Biology (BIMSB). "Our goal is to find a way to treat these patients before the motor neurons die."

New technologies

Using cells from ALS patients, Gouti and her team will grow 3D organoids, which are miniature organ-like structures. Gouti and her colleagues recently developed a way to generate extremely advanced neuromuscular organoids that contain all critical cell types involved in the formation of functional neuromuscular junctions. In these organoids, motor neurons instruct the muscles to contract, just like in the human body. The researchers will generate organoids both with and without the ALS mutations, but otherwise have the exact same genetic background. The organoids provide a reliable in vitro model that allows scientists to study the disease from the very beginning, something that is not possible in human patients because ALS is often diagnosed quite late.

Rajewsky and his lab will sequence the organoid tissue samples at different development stages to drill down into what's going on at the RNA level. RNA's main job is to translate DNA in proteins, so mutations affecting RNA can sometimes lead to non-functional or even harmful proteins. The researchers are particularly curious about mutations in RNA and proteins associated with mysterious clumps inside the cell nucleus called paraspeckles, and if they are somehow responsible for motor neuron death.

Rajewsky's lab will use some of the latest sequencing technologies: long read sequencing, which spells out all the RNAs present in the organoid; single cell RNA sequencing, which matches RNAs with the cell types expressing them, such as skeletal muscle or motor neuron; and spatial transcriptomics, which maps where cells and RNAs are physically located throughout the organoid. Combining these different tools will provide a detailed understanding of RNA activity in space and time.

"Each technology by itself has been well validated, but coming up with robust ways to combine them will be challenging," says Dr. David Koppstein, a postdoctoral researcher in the Rajewsky lab who helped conceive of the project.

Scientific network

The Chan Zuckerberg Initiative, founded by Dr. Priscilla Chan and her spouse Facebook CEO Mark Zuckerberg, supports science and technology with the mission to cure, prevent or manage all diseases by 2100. The CZI Neurodegeneration Challenge Network specifically aims to advance understanding of neurodegeneration, by bringing new ideas, tools and talent to the field, and fostering interdisciplinary collaboration around the world.

The network's Collaborative Pairs Pilot Project Awards provide $150,000 USD to teams led by two principle investigators. One PI must be an early- or mid-career researcher, and the team cannot have received funding for a joint project before. The initiative is funding up to 30 teams in this round. After the first year, successful teams will be eligible to compete for a second funding phase, which provides $1.6 million USD over four years to each team selected.

"In order to find solutions for such difficult, devastating diseases, you need people from many different areas of expertise exchanging ideas," Gouti says. "We are looking forward to this new collaboration and interacting with others in the CZI network."

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