Data Transfer Inside the Cell

Ever since the COVID pandemic, mRNA has been a familiar term for most of us. But it is so much more than a laboratory-designed vaccine. It comprises the universal blueprint for the production of vital proteins in the cell. But what does this essential transport molecule even look like? Until now, the messenger RNA has been depicted in biology textbooks as being stretched out, like a string. “Researchers in the field knew that this could not be the case. But for a lack of a better model, science held on to this concept”, says Clemens Plaschka, whose scientific work was the first to yield visual images of messenger RNA. Indeed, they show a compact spherical structure instead of a curled string. “Our work updates the textbook view of mRNA – with a number of consequences, for example, with respect to mRNA biogenesis, i.e., how it is made; in regard to the transport of the genetic information, as well as the dissolution of the molecules after they have delivered the information for the composition of the proteins to the cytoplasm”, explains the PhD biochemist from the Research Institute of Molecular Pathology (IMP) in Vienna.

The black box of molecular biology
But first, a bit of background: DNA contains all the encrypted information that is needed to build a cell, and it is located inside the cell’s nucleus. For gene expression, in layman’s terms: for the export of these data, the mRNA functions as a messenger that reads the protein blueprints encoded within the genes and subsequently transports these from the nucleus to the cytoplasm. The cytoplasm is the cellular structure in which the complex protein molecules are then built. Without proteins, life is not possible, which explains the significance of this multi-step process.
The way in which cells organize themselves so that only correctly matured messenger RNA will leave the nucleus has so far been a complete black box within the field of molecular biology. Over a period of five years, Plaschka and his team studied how the right messenger RNA is identified and prepared for exit from the nucleus. The team was not only the first to visualize the messenger RNA and show that it forms compact three-dimensional spheres before leaving the nucleus; thanks to state-of-the art cryo-electron microscopy, they were also able to find out how the spliceosome, a kind of molecule-machine, reverts back to its components after its job of modifying, i.e., preparing the mRNA for protein production, is done. “We noticed”, says principal investigator Plaschka, “that deconstruction is only initiated once cleared by a sophisticated safety mechanism.” This is a complex process, “comparable to multi-factor authentication in IT security.”

Elation at the summit
A true scientific breakthrough – which the young scientist himself, who grew up bilingual in Vienna and Chicago, did not expect. “But I do love challenges that I can sink my teeth into”, says the 35-year-old. Solving a difficult problem is like mountaineering: arriving at the top, the warm feeling of happiness sets in only after a long climb.
Plaschka also credits his childhood and school years for his drive for discovery. In his final year in high school, two really great teachers had awakened in him his passion for science, one a biology teacher, and the other a chemistry teacher, which led him to enter a university biochemistry program. This is where he discovered the ability of structural biology to truly explain facts, through depictions of molecules as 3D models. “I was hooked”, remembers Plaschka; as a fan of three-dimensional video games he now had the tools to approach scientific topics in a three-dimensional way. “Scientific problems became tangible for me”, he says, gesticulating.
Plaschka was immediately fascinated by the many unknowns in the field of gene expression. “It was all about the nucleus, meaning, the location of the DNA, and the production site of mRNA”, says the researcher. His father, a professor of economics in the US, had roused his zest for rational argumentation early on: “My brother and I always had to try and find an even better argument in the discussion.” His father very much supported independent thought, along with the occasional unconventional approach. This may have been the reason he embraced this rather unwieldy topic, surmises Plaschka. “It motivates me to solve scientific problems that I consider substantial and answer truly difficult questions.”

Questions, and more questions
Clemens Plaschka considers his scientific contribution to be basic science; it does not offer a final answer to the field but rather “opens up new areas”. “One important result influences the way of thinking of the entire field”, summarizes Plaschka. This field, cell biology, is vast, and many questions remain unanswered. While it is known what the small hole looks like through which the messenger RNA maneuvers itself from the nucleus through the nuclear membrane into the cytoplasm, “we don’t have a very good idea how exactly the mRNA moves through this small hole”, explains Plaschka. Does it transform from the spherical shape into an elongated shape? And how is it possible that this transfer only ever occurs in one direction – from the nucleus towards the cytoplasm? Plaschka: “I am interested in a better understanding of these processes which are so essential to human life.”