Insights of Prof. Michael Sattler Unlocking the Future of Personalized Medicine
Interview with Prof. Michael Sattler, Director of the Molecular Targets and Therapeutics Center at Helmholtz Munich, exploring the impact of understanding molecular disease mechanisms and advancing personalized therapies.
Interview with Prof. Michael Sattler, Director of the Molecular Targets and Therapeutics Center at Helmholtz Munich, exploring the impact of understanding molecular disease mechanisms and advancing personalized therapies.
“Understanding the three-dimensional structure of molecular targets allows to rationally design small molecule drugs. This is a bit like finding a specific key to open a door. Without having a picture of the lock it is very difficult to manufacture a fitting key.”
Prof. Michael Sattler, Director of the Molecular Targets and Therapeutics Center
In what ways does a deep understanding of molecular disease mechanisms enhance the development of personalized therapies?
MS: A precise understanding of molecular mechanisms underlying disease has important implications: We can identify novel biomolecules (proteins, RNA) that are altered in disease, for example, by genetic mutations, as molecular targets for drug discovery. This will be important for developing novel small molecule drugs, but also engineering therapeutic proteins or antibodies.
Understanding the three-dimensional structure of these molecular targets allows to rationally design small molecule drugs. This is a bit like finding a specific key to open a door. Without having a picture of the lock it is very difficult to manufacture a fitting key.
Depending on the target and specific disease-linked mutations, which can be different for each person, a specific, personalized key needs to be developed to fit the new lock. This is for example very relevant for cancer therapy, where over time, new disease mutations develop in patients.
Cozyta - stock.adobe.com“Drug discovery is revolutionized by artificial intelligence and deep learning approaches, greatly accelerating rational small molecule drug discovery and protein design and reengineering.”
Prof. Michael Sattler
What are some of the biggest challenges in developing drugs tailored to individual patients?
MS: A huge challenge is the fact that most of currently available drugs target only a small fraction of the proteins encoded in our genome, and possibilities of finding new protein targets are largely exhausted. Therefore, we need to identify completely novel drug targets, e.g. discover new possible locks, for which we can tailor individual keys.
Another challenge is posed by escape mutations that occur frequently in cancer patients under therapy, which leads to relapse of the disease. Here, a very fast development and optimization of a drug is required to adjust a given key (drug) to a modified lock (target with new mutation).
There are many inherited genetic diseases, for which no efficient therapy is available. Novel concepts to develop therapeutic approaches are thus important. A recent impressive example is highlighted by the approval of an orally available small molecule drug to treat Spinal Muscular Atrophy. SMA is an inherited genetic disorder, for which no therapy has been available until an innovative therapeutic concept was recently developed by modulating RNA splicing.
This video shows a DNA chain and chemical hexagon bonds animation.
What is RNA Splicing?
RNA splicing is a crucial process in biomedical research. It involves the modification of pre-mRNA (precursor messenger RNA) by removing non-coding regions called introns and joining coding regions called exons. This editing process is essential for creating mature mRNA, which can then be translated into proteins.
Looking ahead, how do you anticipate the landscape of personalized medicine evolving over the next decade?
MS: There are many opportunities, to develop innovative therapeutic approaches for personalized medicine, that are based on a precise understanding of molecular mechanisms:
Non-coding RNAs are transcribed from about 90% of our genome (while only 1.5% of our genome encodes proteins) and are often linked to human disease, including cancer, offering unique opportunities as drug targets. Also, detailed understanding of the regulation of RNA splicing mechanisms enables the discovery of novel splicing modulating drugs.
Exploiting dynamic states or targeting intrinsically disordered regions in biomolecules (proteins, RNAs) offer exciting novel opportunities to develop novel therapeutic concepts.
Drug discovery is revolutionized by artificial intelligence and deep learning approaches, greatly accelerating rational small molecule drug discovery but also the design and engineering of therapeutic proteins. Optimized in silico drug design will help to predict the best cancer treatment depending on the cancer mutations of an individual person.
Structural biology and AI greatly accelerate approaches to develop gene therapies by tailored optimized proteins for personalized genome editing.
But, these are just some examples of therapeutic approaches and modalities, which will greatly advance the development of personalized medicines.
Helmholtz Munich | ©Sattler LabWhat is the impact of Splicing?
Researchers have launched a new project to study how this machinery can be controlled with molecular precision. This has the potential to revolutionize biomedical research and eventually treat human disease.
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Latest update: June 2024
Find Out More About Prof. Michael Sattler
Michael Sattler studied chemistry and developed novel nuclear magnetic resonance (NMR)-spectroscopy methods to study biological macromolecules during his doctoral studies at the University of Frankfurt. As a postdoc with Steve Fesik (Abbott labs) he employed advanced NMR methods to solve landmark structures of Bcl family proteins involved in the regulation of apoptosis signaling. With his own research group established at the European Molecular Biology Laboratory (EMBL), Heidelberg, in 1997, he pioneered structural biology of proteins and RNAs that play critical roles in eukaryotic gene regulation, such as alternative pre-mRNA splicing in collaboration with Juan Valcarcel (now at CRG Barcelona) and mechanisms of non-coding RNAs.
Since moving to Helmholtz Munich and TUM in 2007 his lab studies the structural mechanisms and functional roles of essential steps in the early assembly and biogenesis of the spliceosome and its regulation. These studies revealed unique insight into the recognition of the key RNA motifs at the 3’ splice site of human introns by essential splicing factors, SF1 (Science 2001) and U2AF (Nature 2011), highlighting how dynamic recognition enables graduated regulation. His lab unraveled the structural basis of the recognition of arginine methylation marks by the Survival of Motor Neurons (SMN) Tudor domain, linked to spinal muscular atrophy disease.
Michael developed efficient protocols for integrative structural biology in solution by combining NMR, small angle scattering, crystallography and cryo-EM and helped to establish high-end infrastructures for structural biology (1.2 GHz NMR, www.bnmrz.org, and cryo-EM).
Current work focusses on structure and dynamics of (long) non-coding RNAs implicated in human disease, their regulation by posttranscriptional modifications (i.e. m6A) and RNA binding proteins, as well as structural dynamics in biological and disease-linked cellular pathways involving the molecular chaperone Hsp90 and peroxisome biogenesis pathways.
Insight into structural mechanisms of disease pathways provides the basis for innovative structure-based drug discovery to develop novel therapeutic approaches for human disease, including cancer, genetic disorders, and (neglected) infectious diseases.