Intriguing discoveries in 2023

This year, scientists at IMBA disentangled chromosome dynamics and uncovered how transposons can jump across the species barrier. They developed the first multi-chamber heart organoid model, pioneered a tool for navigating the genome in 3D, uncovered a critical role for a lipid pathway in muscle health, and developed a brain organoid model to explore the effects of mutations on a single-cell level. Here are some of the intriguing discoveries and breakthroughs that came out of IMBA in 2023.

Virus-like transposons cross the species barrier

Scientists have known for decades that genes can be transferred from one species to another, both in animals and plants, in a process called horizontal gene transfer (HGT). However, the mechanism of how such an unlikely event occurs remained unknown. A new study from the laboratory of Alejandro Burga uncovered one of the long-sought vectors of HGT in nematodes: the ancient virus-like transposons called Mavericks.

The team demonstrated that Mavericks are responsible for an event of HGT between two worm species whose genomes are as divergent as those of humans and fish. Burga and his team predict that Mavericks and analogous elements could mediate HGT in a broader pool of animal lineages, including vertebrates.  

“If Maverick-mediated HGT is shown to be broadly applicable to any nematode species, it has the potential to become an invaluable resource. Beyond strict lab and research applications such as the genetic manipulation of non-model nematodes, such a resource could allow us, in the future, to genetically modify parasitic nematode species that might be of agricultural or medical relevance,” concludes Burga.

HiCognition: A computational tool to navigate the genome in 3D

Complex functions such as gene expression, recombination, and chromosome segregation require highly regulated and coordinated folding of DNA inside cells. This organization depends on thousands of proteins and chemical modifications that determine chromatin structure. However, it is complex to establish a direct link between 3D genome organization and physiological function, as many factors are involved and genomic regions vary highly.

Researchers from the laboratory of Daniel Gerlich developed HiCognition, a visualization and machine-learning tool that allows biologists to navigate large, multi-dimensional genomics data. HiCognition combines an interactive visualization interface with high-performance data processing, statistical tools, and machine learning. HiCognition’s fast and computationally efficient implementation allows real-time browsing through thousands of genomic regions.

“This tool will provide researchers with opportunities to understand fundamental mechanisms that influence genome structure and function,” says Gerlich.

First multi-chamber heart organoids developed

Heart disease kills 18 million people each year, but the development of new therapies faces a bottleneck: no physiological model of the entire human heart exists – so far. In 2023, Sasha Mendjan and his team achieved a breakthrough: The laboratory developed a new multi-chamber heart organoid that mirrors the heart’s intricate structure. This new heart model enables scientists to advance screening platforms for drug development, toxicology studies, and understanding heart development.

Using the multi-chamber heart organoids, the researchers have already gained insight into early heart development, particularly how the human heart starts beating – which has not been understood so far. Multi-chamber cardioids also enable researchers to investigate chamber-specific defects.  In a proof-of-principle, the Mendjan team set up a screening platform for defects, in which they study how known teratogens and mutations affect hundreds of heart organoids simultaneously. 

Heart organoids developed from patient-derived stem cells could, in the future, give insight into the developmental defect and how it may be treated and prevented. The Mendjan group is particularly interested in using multi-chamber heart organoids to understand heart development further: “We now have a basis to investigate the heart’s further growth and regenerative potential.”

Muscle health depends on lipid synthesis

Muscle degeneration in inherited diseases and aging affects hundreds of millions of people worldwide. Degeneration of skeletal muscles, the body’s protein reservoir, leads to general physiological decline, a condition called frailty. In 2023, a team of researchers led by Domagoj Cikes and Josef Penninger uncovered the central role of the enzyme PCYT2 in muscle health.

PCYT2 is known as the bottleneck enzyme in a major synthesis pathway of ethanolamine-derived phospholipids, the phosphatidylethanolamines (PEs). Based on patient data and using laboratory mouse and zebrafish models, the researchers showed that mutations affecting PCYT2, or its reduced activity, are conserved hallmarks of muscle degeneration across vertebrates. Specifically, they demonstrated that PCYT2 deficiency in muscles affects mitochondrial function and the physicochemical properties of the myofiber membrane.

“Our current work demonstrates a fundamental, specific, and conserved role of PCYT2-mediated lipid synthesis in vertebrate muscle health and allows us to explore novel therapeutic avenues to improve muscle health in rare diseases and aging,” concludes Penninger.

Single-cell brain organoid screening to identify developmental defects

Using a combination of brain organoid technologies and complex genetics, the laboratory of Jürgen Knoblich and the group of Barbara Treutlein at ETH Zurich, developed a method for identifying the cell types and gene regulatory networks that underlie autism.

With this organoid system, the researchers can comprehensively test the effect of multiple mutations in parallel and at a single-cell level. Using the system, the researchers show that mutations of 36 genes, known to put carriers at high risk of autism, lead to specific cell type changes in the developing human brain.

In addition to gaining unparalleled insights into the pathology of autism, the organoid system is highly versatile and transferable. “We anticipate that our technique will be widely applied beyond brain organoids to study various disease-associated genes,” says Knoblich.

A cohesin-regulated tug-of-war inside chromosomes

Cohesin, a ring-shaped protein complex, tethers the two DNA copies contained in each replicated chromosome such that they can be properly moved during cell division. The laboratory of Daniel Gerlich showed in a new study that a subset of cohesion complexes, known for its ability to extrude DNA loops, also facilitates the separation of duplicated DNA molecules. These findings support the notion that DNA loop extrusion is an evolutionarily conserved mechanism, promoting the segregation of replicated genomes into daughter cells.