Müller Ulrich

The FPA Scientific Grand Prize 2024 is granted to Professor Ulrich Müller. He is awarded the prize for discovering the function of the genes encoding the complex cellular machinery which allows inner ear sensory cells to transform soundwaves into electrical signals interpretable by the brain. This work paved the way for the development of therapies for genetic forms of deafness. Promising clinical trials are currently underway.

Ulrich Müller is the Bloomberg Distinguished Professor of Neuroscience and Biology, and the Director of Developmental Neuroscience at the Johns Hopkins University School of Medicine in Baltimore (United States).

His Work

Professor Müller has devoted his research to the identification and study of the components of the mechanotransduction machinery of hair cells – i.e. the molecular mechanisms by which these cells in the inner ear convert mechanical sound waves into electrical signals to provide our sense of hearing. Defects in this complex machinery cause deafness, the most common form of sensory impairment in humans.

What happens when sounds arrive in the inner ear? Specialized cells named “hair cells” sense these sound signals (Figure A). The cells have their name because they are crowned on top with hair-like protrusions, the so-called “stereocilia”, which are attached to each other by thin filaments, the tip links (Figure B). When a sound wave reaches the stereocilia, they are bent by the vibration and this movement leads to the opening of ion channels – named “mechanotransduction channels or MET channels” – located in the hair cell membrane and attached to tip links. The entry of ions via this channel triggers the release of chemical molecules from hair cells onto neurons that are connected to the hair cells. This generates electrical signals, which are then propagated throughout the brain to mediate the sensation of hearing.

Identifying the pieces of the hair cell machinery

When Professor Müller started his research, the principles underlying the process of mechanotransduction were well known but the molecules that regulate this process had not been discovered. His major contribution was to identify many of these molecules: his laboratory used genetics, molecular biology and electrophysiology to dissect, step by step, the function of the genes encoding the proteins of the mechanotransduction machinery of hair cells. To conduct these experiments, his laboratory generated a large number of mouse lines carrying mutations and also collected additional mouse lines from collaborators. His laboratory identified genes that cause deafness and are required for mechanotransduction by hair cells, a painstaking process and a huge task. Notably, his laboratory discovered that two of the genes encode proteins that form the tip link (CDH23 and PCDH15), and that an additional protein (LHFPL5) couples the tip link to the mechanotransduction channel. His laboratory also demonstrated that the mechanotransduction channel itself is encoded by several genes and his laboratory characterized three of the MET channel proteins (TMIE, CIB2, CIB3) as well as components of the upper tip-link (Harmonin, Sans and MYO7A proteins) that interact in a complex with CDH23 to regulate mechanotransduction and tip-link tension (Figure C). Today this work is still in progress because of the unexpected complexity of this machinery.

New therapeutic approaches for the treatment of deafness

Notably, the mouse and human genomes are very similar and gene mutations that cause deafness in mice also commonly cause deafness in humans. Feeling a responsibility to develop applications for patients, Prof. Müller gradually started to work more closely with clinicians. He co-founded a biotechnology company, Decibel Therapeutics, dedicated to discovering and developing treatments to restore and improve hearing and balance. Decibel, now bought by Regeneron, has been conducting since 2023 a gene therapy* clinical trial in deaf children with the DFNB9 genetic disease caused by mutations in the gene encoding Otoferlin, a protein contributing to the transmission of signals from hair cells to neurons. The first results of the gene therapy trial are very promising. Similar trials are underway around the world, one developed by the French biotech company Sensorion**.

Prof. Ulrich Müller’s discoveries not only shed light on some of the fundamental mechanisms of hearing, but they also revealed numerous potential therapeutic targets useful for the development of innovative medical solutions to treat hearing loss, a line of research he would like to continue in the future. His biggest hope today is that children will be able to hear again thanks to scientific advances and that other diseases such as age-related hearing loss and tinnitus will also be treatable in the future.

* Treatment of a genetic disease by delivering the normal gene to compensate for the abnormal gene causing the disease or correcting the abnormal gene

** FPA, Institut Pasteur and AP-HP are partner of the academic consortium called RHU Audinnove related to this trial.