Explore the journey of Claudia Höbartner, a distinguished chemistry professor at the University of Würzburg, as she delves into the intricate world of RNA. With a focus on modified nucleotides and functional nucleic acids, Höbartner’s groundbreaking research has unlocked new insights into the diverse functions of RNA and its potential applications in various fields. Discover how her work is reshaping our understanding of RNA’s role in health, disease, and therapeutics, and how she’s using innovative tools to illuminate the hidden complexities of this essential molecule.
Which wall does your research break?
A large part of the human genome is transcribed into RNA, but only a small fraction is then translated into proteins. Therefore, a large diversity of noncoding RNAs is formed, which is still full of surprises in terms of their structures and functions. The molecular composition of RNA as a linear biopolymer is rather simple, but a large diversity of posttranscriptional RNA modifications adds an extra layer of complexity. The available methods for studying RNAs’ structures, functions, localizations, metabolisms, and regulatory roles are still rather limited, compared to the methods available for studying proteins. Our research builds upon the ability of the linear RNA biopolymer to fold into complex three-dimensional structures. These structures are the basis for its many roles in biology, but in addition, the formation of three-dimensional RNA structures enables new functions, for example, to specifically recognize other molecules or to catalyze chemical reactions. Such RNA catalysts are called ribozymes. Our research projects contribute insights into the diversity of RNA functions by developing RNA-based tools for RNA labelling and bioorthogonal modification. This includes ribozymes and aptamers. These tools will allow us to visualize RNAs directly, and will help us to explore their fate, localization, transport and interactions with other molecules. We are particularly interested in exploring the ability of RNA to catalyze the installation of natural RNA modifications, such as methyl groups. Being able to install native RNA modifications by ribozymes instead of protein enzymes is of fundamental interest for understanding the evolution of functional RNAs and the functional roles of posttranscriptional modifications. In addition, we foresee new applications of ribozymes to rescue RNA modification states when the responsible proteins are not available or dysfunctional, for example, due to mutations. In order to find new catalytic functions of RNAs and to develop new ribozymes, we are also advancing in vitro selection methods and the analysis of enriched nucleic acid libraries. These developments are expected to break the wall to the rich functional and structural information hidden in the RNA sequence space and the fascinating plasticity of this seemingly simple linear biopolymer RNA made of four building blocks.
What inspired or motivated you to work on your current research or project?
A large part of the motivation comes from my fundamental curiosity about the molecular mechanisms of life, and in particular about RNA and its roles and modifications. As mentioned above, the chemical diversity of natural RNA modifications goes far beyond the four standard letters (i.e., nucleotides) A, C, G, and U. While RNA is initially synthesized from these four building blocks by polymerases, other enzymes (often called writer enzymes) decorate certain positions with small chemical modifications, and I would like to understand more about their roles for the diverse functions of RNA. Among RNA modifications, methylated nucleotides belong to the most evolutionary conserved features of modified RNAs. Many of them occur at functionally identical positions throughout all domains of life. This suggests that they provided an early benefit during evolution, and it is an exciting question to address, how such modifications were installed and maintained, given that they cannot be directly inherited but need to be synthesized de novo on any newly generated RNA. Thus, there must be a hidden layer of instructions, when, where and how an RNA gets modified. By uncovering some of the little secrets of life and evolution, we will generate knowledge that may also help us in the development of targets or strategies to understand and combat the development of cellular misfunction and disease. Besides the fundamental roles for RNA structure and function, modified nucleotides have also been in the focus of general interest for their importance to nucleic acid therapies. Indeed, modified nucleotides are essential constituents for all kinds of RNA therapeutics. This includes antisense oligonucleotides and siRNAs, for which mostly backbone modifications play a big role to enhance the affinity to the target mRNA and to enhance stability and prevent undesired degradation by nucleases. Another very important field for the application of modified nucleotides is the area of mRNA vaccines, where a slight variation of the constitution in one of the nucleobases played a decisive role in their success. Moreover, chemically modified nucleotides have been the focus of antiviral research for many years, for example, as inhibitors of viral RNA polymerases. Only recently it was discovered that human cells can endogenously generate modified nucleotides that play a role in antiviral defense mechanisms. This is another example of inspiration and motivation to continue our research on ribozymes and nucleic acid modifications.
In what ways does society benefit from your research?
The breakthrough in ribozyme research and the finding that RNA can catalyze the synthesis of modified nucleotides is of fundamental interest in basic research. Its potential impact may unfold in several different directions. We can imagine many practical applications, first still within the realm of exploratory research in chemical biology, but this may also extend to therapeutic applications in the future. There are many examples in the recent past that demonstrate how fundamental discoveries in RNA biology transitioned into potential applications for the benefit of society. We expect that ribozymes and other functional RNA devices generated in the laboratory may easily find applications in diverse disciplines to enlighten our understanding of cellular RNA functions in health and disease. We also envision catalytic RNAs as active components for future diagnostic and therapeutic applications.