In memoriam: Lelio Orci

Alain Perrelet, Roberto Montesano 

 

We were very saddened by the death in Geneva, on 22 October 2019, of honorary Professor Lelio Orci, a prominent member of the Swiss and international cell biology community. Lelio Orci devoted all his scientific life, day and night often, to the identification and quantitative analysis of the components of cells and tissues and their mutual interactions. He will be remembered as a tireless and inventive researcher who brought to the highest level the art of quantitative electron microscopy for studying the relationships between cell structure and function.

From his native town near Rome, Lelio Orci, a freshly graduated physician, reached Geneva in 1966 at the driving wheel of a white Fiat Cinquecento. He joined Professor Charles Rouiller, then holder of the Chair in Histology and Embryology at the Faculty of Medicine of the University of Geneva. From the onset of his scientific activity, Lelio Orci realised the outstanding potential of the recently installed electron microscope, which enabled the analysis of cell architecture with one hundred times more detail than a conventional optical microscope. Using this powerful instrument, he investigated, with an acute and critical eye, a wide spectrum of relevant issues in histology and cell biology, ranging from the secretion of insulin by the beta-cells of the endocrine pancreas to the internal structure of cell membranes. With his team, Lelio Orci complemented electron microscopy with immensely valuable techniques, such as pulse-chase autoradiography and quantitative immunogold labelling. He also pioneered the application of the freeze-fracture methodology to visualise the organisation of plasma membranes, in particular the topographical distribution of transmembrane proteins in the specialised sites of intercellular junctions.

Endowed with this large variety of technical tools and personal skills, Lelio Orci succeeded in precisely elucidating the intracellular path of the hormone insulin in the pancreatic beta-cells under a variety of experimental conditions. Thus, he demonstrated that, during its journey from its site of synthesis (as precursor proinsulin) in the endoplasmic reticulum to the site of release in the extracellular space as mature insulin, the hormone migrates enclosed in vesicular membrane compartments. Here, proinsulin is enzymatically cleaved into insulin within a clathrin-coated, acidic compartment of the Golgi apparatus, which subsequently gives rise to mature secretory granules ready for hormone secretion. These landmark achievements, among many others, coupled with the unequalled production of a scientifically and aesthetically exemplary iconography, raised Lelio Orci very early to the status of the most talented electron microscopist of his generation. This reputation went far beyond the Swiss borders, and brought him into numerous and fruitful collaborations. Two in particular, woven in the USA with two renowned American researchers, James (Jim) Rothman in Yale and Randy Schekman in Berkeley, led to the successful association of morphology by Lelio, biochemistry by Jim and genetics by Randy. This methodological integration enabled the identification and characterisation of the mode of formation of the intracellular membrane compartment (vesicles) responsible for the transport of proteins from the endoplasmic reticulum to the Golgi and in reverse direction from the Golgi to the endoplasmic reticulum. In these processes, vesicles were shown to bud from the donor compartment owing to the assembly of specific membrane coat proteins: COP I (discovered by Jim and Lelio) for retrograde transport, and COP II (characterised by Randy and Lelio) for anterograde transport. On reaching their acceptor compartment, COP coats disassemble to let the respective bare membranes fuse, allowing cargo to be released. The specificity of these molecular mechanisms proved valid for the intracellular transport of virtually all proteins, including insulin.

In this attempt to portray Orci’s scientific legacy, we dwelled only on the two above-described major contributions; but for those who would like to dive deeper into Lelio’s exceptional creativity, it will suffice to browse through the list of nearly six hundred publications and eighteen major awards or distinctions (including an honorary doctorate from the University of Geneva) which illustrate his curriculum vitae, in addition to the coveted status of foreign member of the National Academy of Sciences of the USA.

As a professor, and later chairman of an academic department of the Faculty of Medicine, Lelio Orci set very high standards for research, intellectual self-criticism and the quest for technical excellence. With his passionate teaching and uncompromising requirements for flawless scientific conduct, Lelio Orci successfully trained numerous doctoral and post-doctoral students, many of whom have since pursued distinguished academic careers throughout the world. They are now orphans, but they will never forget what they owe to their mentor.

 

Alain Perrelet, Honorary professor, Faculty of medicine, University of Geneva, Switzerland

Roberto Montesano, Honorary professor, Faculty of medicine, University of Geneva, Switzerland