Ciechanover starts his lecture with general remarks about the relevance of inspiration and the evolvement in science in general. He wants to show the logical development of science taking his own experience as an example. He talks about the synthesis and degradation of proteins, the chemistry of proteolysis in the body, and the reasons for degradation. The lecture continues with a remark on the founding fathers of the field mentioning especially the consequences for scientific research of the migration of Jewish scientists from Nazi Germany to the US. Rudolf Schoenhammer was the first scientist to postulate that intracellular proteins were not static (“dynamic state of body constituents”). Professor Ciechanover continues with the discovery of the lysosome and first experimental evidence that intracellular protein degradation has nothing to do with lysosomes and thus requires a different mechanism. Hershko and Ciechanover worked with reticulocytes which are free of lysosomes and discovered that the Ubiquitin system (with its many components) is acting as a marker for intracellular protein degradation and the degradation of proteins with a poly-Ubiquitine chain is actually taking place at the proteasome. Ciechanover describes the Ubiquitin-proteasome system as a “post-translational modifying system in which the modified substrates are being targeted to different purposes”. A very important application is “the translation of the system into drugs” and a few examples are presented. The lecture closes with “Nature is complex, but the beginnings of discoveries are always simple”.
Between the 50s and 80s, most studies in biomedicine focused on the central dogma - the translation of the information coded by DNA to RNA and proteins. Protein degradation was a neglected area, considered to be a non-specific, dead-end process. While it was known that proteins do turn over, the high specificity of the process - where distinct proteins are degraded only at certain time points, or when they are not needed any more, or following denaturation/misfolding when their normal and active counterparts are spared - was not appreciated. The discovery of the lysosome by Christian de Duve did not significantly change this view, as it was clear that this organelle is involved mostly in the degradation of extracellular proteins, and their proteases cannot be substrate-specific. The discovery of the complex cascade of the ubiquitin solved the enigma. It is clear now that degradation of cellular proteins is a highly complex, temporally controlled, and tightly regulated process that plays major roles in a variety of basic cellular processes such as cell cycle and differentiation, communication of the cell with the extracellular environment and maintenance of the cellular quality control. With the multitude of substrates targeted and the myriad processes involved, it is not surprising that aberrations in the pathway have been implicated in the pathogenesis of many diseases, certain malignancies and neurodegeneration among them, and that the system has become a major platform for drug targeting.