Biochemistry in the first 60 years of the 20th century mostly consisted of the identification of the main components of the living cell, its elementary metabolites, the principal enzyme reactions of intermediary metabolism, and their genetic characterisation as proteins. The extension to the cell of Claude Bernard's concept of constancy of the internal environment (milieu intérieur) and of its control (as for instance in glucose homeostasis) that was initially conceived for the whole organism, introduced the regulation of cellular metabolism as a fundamental topic of biochemical research. Enzyme adaptation in bacteria—the transient increase, or decrease, of enzyme production in response to a specific nutrient—became a model to investigate biological regulation at the gene level and was soon shown to result from a regulation of gene expression at the transcriptional level.1 In parallel, the regulation of enzyme activity by covalent phosphorylation and dephosphorylation was demonstrated as a major alternate mechanism of metabolic regulation in higher organisms, specifically in the case of glycogen metabolism.2, 3 Also, in the 50s, the cybernetics and control theory perspective became influential in the understanding of metabolic regulation of living organisms, bacteria in particular, and was familiar to Jacques Monod. Quantitatively measuring the rates of amino acid synthesis in Escherichia coli (E. coli) with the chemostat, Novick and Szilard4 revealed that the synthesis of the tryptophan precursor indole-3-glycerol phosphate is rapidly inhibited by added tryptophan. As a consequence, they postulated that an enzyme early in the pathway was feedback-inhibited by the end product of the biosynthetic chain. In parallel, Adelberg and Umbarger,5 investigating the biosynthesis of another amino acid valine, noticed that in a valine-requiring mutant of E. coli the secretion of an intermediate of valine biosynthesis—alpha keto isovaleric acid—was inhibited by valine, the end product of the pathway. Umbarger6 then discovered that, in cell free extracts, the first enzyme of the biosynthetic pathway of L-isoleucine, L-threonine deaminase was feedback-inhibited by L-isoleucine. A similar finding was reported by Yates and Pardee7 for the pyrimidine biosynthetic pathway where the first enzyme, aspartate transcarbamylase, is feedback inhibited by the pyrimidine, cytidine triphosphate (CTP), that E. coli produces after a sequence of seven further reactions. Later, Earl Stadtman and George Cohen,8 elucidating the original case of branched biosynthetic pathways of the amino acids threonine and lysine, discovered a dual feedback inhibition of the first step catalysed by aspartyl kinase by the two end products, threonine and lysine.