I wish to take advantage of the special circumstances in which this communication is delivered for reviewing 25 years of researches aimed to increase our understanding of vesicular exocytosis. This quest was launched together with Mark Wightman and been initially performed in close connection with him across the Atlantic, then in my ENS group alone or within successful collaborations involving among a few others Andy Ewing and more recently Weihua Huang. Most research lectures concentrate on the most recent views or achievements. This is certainly fine and highly important since this allows disclosing the most relevant information to peers but, somewhere, it hides the fact that a real academic research cannot be planned as a linear process but is, and hopefully will always remain, a fully creative art fueled by an unending interplay between passion and desire of unravelling Nature’ secrets.

I met Mark while I was spending a year at Indiana University as a Visiting Assistant Professor with Jay K. Kochi and we often chatted when having a cigarette together (yes at the time one could smoke in his/her office or lab hallways!) about microelectrodes. This is how we paired our different skills to establish this field as one of the main pillars of electrochemistry today. However, what thrilled me most in our discussions was his researches on brain – while, I must confess, this frightened me a bit at the same time.

Since my middle school time I had been fascinated by the brain, this biological machine WHO is the real and only US. At the time, our biology teacher could not explained a lot to us about its mechanisms but what she told us was nonetheless sufficiently thrilling to captivate the 15-year old kid I was at the time. Exactly 15 years after this forgotten desire was revived when I met Mark. Following Adams’ trace, he was showing that one could really investigate the brain with electrochemistry. We did some highly cited works in this direction during the next decade, but I rapidly discovered that my real journey in the area would not be of investigating the brain behavior but would rather focus on trying to understand why Nature selected such strange contraptions called synapses to transfer nerve influxes between two neurons or between a neuron and e.g. a muscle cell. Indeed, while in the nineties analytical chemists could barely quantify packets of billions of small molecules, the brain relies exclusively on transferring its critical information through bursts of only a few thousand small transmitters molecules. Understanding why and how the brain could do it led to the design of the “artificial synapse”. This opened the route to precise measurements and quantification of vesicular release kinetics.

Since then we, and the large community inspired by these researches, made immense progresses. We progressively had to forget our initial necessary, but too simplified, views to reach the present delicate level of detail and knowledge. Yet, I am sure that we are only starting to discover the real complexity and the origin of the magic performance of vesicular release.