How the Nanobody expertise of Jan Steyaert's lab contributes to new discoveries.
2018 was a year full of highlights for Jan Steyaert (VIB-VUB Center for Structural Biology) and his research team, with two papers published in Cell and four in Nature. The trend continues in 2019, with two Nature publications, one Cell paper and a key technology licensing agreement already in the books.
The main focus of Jan’s lab – single-domain antibodies, known as Nanobodies® – has proven indispensable to the scientific and commercial goals of a range of different partners in Belgium and abroad. These high-impact research avenues highlight the fact that excellent science isn’t done in a vacuum: collaborations with other institutes and industry players are essential to VIB’s impact on the world.
Nanobodies get an upgrade
Nanobodies, which were discovered over two decades ago by VUB scientists, can be used to study the molecular shapes of proteins, which contributes to detailed insights into disease markers and more effective therapies. The success of these tiny antibody fragments has given rise to multiple Belgian VIB spin-offs in the last few years, including AgroSavfe, Ablynx and Confo Therapeutics.
Thanks to Jan and his team, Nanobodies recently underwent a major makeover that responds to new technological needs with commercial applications. While their small size is often an advantage, other applications – such as cryo-electron microscopy, or cryoEM – require scaled-up versions of the antibodies. CryoEM generates high-resolution ‘images’ of the structures of biomolecules, which is especially useful in the study of drug interactions.
“Small proteins don’t provide enough contrast in cryoEM images,” Jan elaborates. “Larger, less flexible Nanobody configurations are needed to be able to see protein structures with precision.” Responding to this need, Jan’s team developed ‘scaffolds’ that keep the fused Nanobodies rigidly in place – called Megabodies, and published three papers on their results.
VIB-VUB spinoff Confo Therapeutics immediately recognized the value of these Megabodies, entering into an exclusive global licensing agreement with VIB. “Megabody technology will give us an outstanding toolbox for drug discovery,” asserts Cedric Ververken, CEO of Confo Therapeutics.
The atomic workings of mitochondria
As the famous quote by biologist Philip Siekevitz goes: “The mitochondrion is the powerhouse of the cell.” Because mitochondria are so crucial to our existence on a molecular level, any disfunctions in the mechanisms that drive them are linked with many diseases. As a result, these tiny cellular structures are the subject of intense scientific scrutiny. The best tools to study them? Nanobodies.
In collaboration with the Nanobody ninjas of the Jan Steyaert lab, and with the assistance of Diamond Light Source (Harwell, UK) and the European Synchrotron Radiation Facility (Grenoble, France), scientists from the MRC-MBU in Cambridge, UK used nanobodies to shed light on the proteins that shuttle compounds in and out of mitochondria.
The researchers zoomed in on a protein responsible for carrying about 50kg of ADP and ATP (substances needed to fuel cells) per day through a membrane that surrounds the mitochondria so that it can be consumed. Nanobodies and X-ray crystallography were used to determine the molecular structure of this carrier protein, revealing how it is able to change its shape to transport ADP and ATP without allowing other small molecules to leak through the mitochondrial membrane.
“These results are especially groundbreaking because it’s likely that other carrier proteins work in a similar way,” Jan asserts. “For the first time, we have seen how genetic mutations affecting these proteins cause a range of neuromuscular, metabolic and developmental diseases. This leads to new opportunities in the search for effective treatments.”
These are just a few recent examples of how cutting-edge VIB expertise and discoveries both fuel and are fueled by collaborations between institutions, industry players and universities. The cross-border transfer of knowledge – and the specific resources needed to translate discoveries into society-changing products – is ever more essential to VIB’s future and the future of the global life sciences ecosystem as a whole.
Laverty et al., Nature 2019
Masiulis et al., Nature 2019
Uchanski et al., bioRxiv 2019
Ruprecht et al., Cell 2019