It was long thought that RNA merely mediates protein synthesis. But by now it is abundantly clear: these molecules perform many more tasks in the body. As part of the new NUCLEATE Cluster of Excellence, LMU researchers led by Veit Hornung are investigating how RNA and DNA could be used for novel therapies and innovative biotechnologies.
Some scientific discoveries quietly pave the way for revolutions. Shortly after the turn of the millennium, biochemist Katalin Karikó and immunologist Drew Weissman investigated a puzzling observation: Why did RNA produced in the laboratory trigger potent immune responses, while the body's own RNA remained completely harmless? Their experiments led to a crucial discovery: natural RNA carries small chemical modifications that prevent it from being recognized as foreign by the immune system. When Karikó and Weissman transferred these changes to artificial RNA, they succeeded for the first time in introducing it into cells without provoking an immune response. No one suspected that this inconspicuous result would one day transform modern medicine.
The medical scientist and biochemist Veit Hornung investigates how our immune system identifies and neutralizes intruders.
© Stephan Höck / LMUBut some experts were already pricking up their ears. They saw enormous medical potential in tricking the immune system into using nucleic acids for specific medical purposes. Among them was Veit Hornung, who was a young assistant at LMU at the time. The medical scientist and biochemist investigated, then as now, how our immune system identifies and neutralizes intruders. “A significant component of these defenses is the recognition of nucleic acids,” he explains. RNA and DNA, the two main types of nucleic acids, serve as carriers of genetic information for all organisms, acting as the ‘blueprints of life’, so to speak.
When pathogens enter the body, they leave traces of their genome or their gene expression activity – that is to say, residues of DNA and RNA molecules. Immune cells recognize these snippets of foreign genetic information and dismantle them. The biomolecule we mentioned at the outset was a specific form of RNA known as messenger RNA, or mRNA for short. Cells use these molecules as a sort of construction manual for proteins. First, the genetic information contained in DNA is transcribed into mRNA in the cell nucleus, before the copies migrate to so-called ribosomes – the ‘protein factories’ of cells – in the cytoplasm.
Veit Hornung
The idea of using nucleic acids to intervene in this process was therefore obvious: if cells could be artificially supplied with mRNA or similar molecules, the desired proteins could be produced – for example, to treat diseases or replace missing proteins. However, implementation turned out to be difficult. Synthetic mRNA triggered strong immune responses in the body and was broken down before it could take effect.
“That was a huge problem for a long time,” says Hornung. The decisive breakthrough came when Katalin Karikó and Drew Weissman showed how RNA could be chemically modified so that it no longer triggered an immune response. This discovery in 2005 paved the way for mRNA-based drugs – even though it took several more years to develop them.
The flurry of discoveries over the past two decades has triggered a veritable paradigm shift in RNA research. | © Jan Greune / LMU
Because only around two percent of DNA consists of protein-coding genes, experts had assumed for decades that most of it does not serve any purpose. It was disparaged as junk DNA. However, it was revealed bit by bit that large portions of these DNA sequences are also transcribed into RNA. Scientists were perplexed: Why do our cells transcribe seemingly useless DNA into RNA? Accidentally, as some argue?
Not at all: “We now know that the functions of RNA go far beyond its contribution to the manufacture of proteins,” says Hornung. The scientist has followed the extraordinary ‘career path’ of RNA with attention and contributed quite a few insights of his own – from 2008 as Professor of Clinical Biochemistry at the University of Bonn; and since 2015 as Chair Professor of Immunobiochemistry at LMU’s Gene Center Munich. “There are RNA molecules that regulate gene expression, and others that function enzymatically and catalyze reactions in the cell – something that was formerly attributed exclusively to proteins,” says Hornung. “In addition, there are versions that act as second messengers by relaying and amplifying signals within the cell.”
Veit Hornung
Researchers also discovered comparatively long strands of RNA which function as scaffold molecules and bring together protein complexes. And they came across unusually short variants, which they initially took for the genes themselves and not for their copies. The first such microRNA, or miRNA for short, was found accidentally in the roundworm C. elegans, a classic model organism in developmental biology. Since then, scientists have found some 2,000 variants in humans alone. For the most part, miRNA regulates protein synthesis.
The flurry of discoveries over the past two decades has triggered a veritable paradigm shift in RNA research. Some even talk of an ‘RNA revolution,’ like the biologists Jeanne Lawrence and Lisa Hall from the University of Massachusetts Chan Medical School. In an article in the journal Science from 2024, the two justify this bold choice of words by pointing to the demonstration that long-lived RNA molecules are integral parts of neurons. Until then, every RNA was thought to be short-lived. Such persistence clearly opens up a whole range of possible further functions and mechanisms of action for these molecules, many of which have not even been identified yet.
This new understanding has prompted a rethink in clinical research in particular. Among other reasons, this is because non-coding RNAs also play a role in diseases. For example, they influence cellular processes that are involved in the development of diseases like cancer. This makes them possible points of attack for drugs – or they could even be turned into active agents themselves.
The flurry of discoveries over the past two decades has triggered a veritable paradigm shift in RNA research. | © IMAGO / Zoonar / Christoph Burgstedt
To further advance research into RNA and DNA, Hornung and colleagues successfully raised funding for the NUCLEATE Cluster of Excellence – one of the new top-level research alliances in Germany. The program will begin in 2026 at three main locations – LMU Munich, TU Munich, and the University of Würzburg – and further partner institutions. The research strategy is novel: “We want to consider nucleic acids from three perspectives: as a subject, as an object, and as a tool,” says Hornung. As a ‘subject,’ the nucleic acid performs a function that affects the cell – it regulates gene expression, for example, or accelerates a biochemical reaction. As an ‘object,’ something happens to the nucleic acid – it is chemically modified, processed, or broken down. “There are mechanisms, for instance, which modify or repair nucleic acids,” explains Hornung. In these two areas, the NUCLEATE partners chiefly want to practice basic research – for example, in order to decipher unknown functions of RNA and DNA and associated processes in cells.
The third category of ‘tool,’ meanwhile, refers to “the utilization of these functions for practical applications,” says Hornung. This includes therapeutics based on synthetic RNA and DNA molecules which influence processes inside cells in targeted ways – as well as innovative technologies like the genetic scissors CRISPR-Cas. This technique makes use of a natural defense system in bacteria that enables DNA to be precisely manipulated. “We want to discover further CRISPR mechanisms and exploit their potential,” observes Hornung. The ultimate vision is to correct DNA directly in the body in order to heal genetic illnesses. Initial approaches already exist and NUCLEATE plans to further develop them. This includes computer-based methods: “With the help of AI, we would like to better understand cellular processes and predict how certain changes will affect the workings of the cell,” adds the LMU professor.
mRNA vaccine manufacturing facility.
© IMAGO / AAPAlthough the focus of the NUCLEATE Cluster of Excellence is on basic research, the bridge to application has been considered from the beginning. “We deliberately integrated colleagues who work in clinical and translational medicine and develop new therapeutic concepts,” says Hornung. “One decisive step is, for example, the targeted delivery of RNA molecules to the right cells.” As such, the scientists in NUCLEATE will develop new platforms which allow small regulatory RNAs, such as siRNA, to be transported and released in a tissue-specific manner. These innovative delivery concepts should help make RNA therapies safer and more effective – a key factor for their future clinical use.
Where the journey will ultimately take us cannot really be foreseen. To appreciate this, we need only consider mRNA technology. “At the beginning, nobody believed in the method; it was developed in the ‘basement’ as it were.” However, the decades-long foundational work paid off when a virus menaced the world. The first therapeutic RNA application was developed: mRNA vaccines. These induce cells to manufacture the spike protein which is characteristic of the coronavirus. In this way, the immune system becomes acquainted with the pathogen before an infection occurs. As a result, when an infection does occur, the disease takes a significantly milder course.
Veit Hornung
This principle, however, is not necessarily limited to prevention. Researchers are working, for example, on ways of training the immune system to attack tumor cells via mRNA therapy. Furthermore, mRNA approaches are conceivable to treat genetic diseases where a certain protein is missing or defective – cystic fibrosis, say, or metabolic disorders.
“mRNA technology has huge therapeutic potential,” reckons Hornung. And the Nobel Committee was inclined to agree: For the development of the foundations of mRNA technologies, the Hungarian-American biochemist Katalin Karikó and the American immunologist Drew Weissman were awarded the Nobel Prize in Medicine in 2023. And so although RNA research has already changed modern medicine, the true RNA revolution could just be getting started.
Veit Hornung is Chair Professor of Immunobiochemistry at LMU’s Gene Center Munich and one of the spokespersons for the NUCLEATE Cluster of Excellence.
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