Gene dosage effects have always held a fascination for me that I cannot readily explain. Perhaps it stems in part from the fact that I entered scientific research at a time when the concepts of genetic regulation – induction, repression, feedback control, adaptive enzymes – were so much in the ascendency, and yet there were clear examples in humans and other mammals of situations in which these concepts did not seem to apply. Two papers had a great influence on my thinking at the time, one by Augustinsson and Olssen (1961), concerned, strangely enough, with enzyme activities in pigs, and the other by Allison and Blumberg (1958), dealing with dominantly and recessively inherited disorders in humans.

Despite my intellectual fascination with gene dosage effects and related matters, I did not, aside from a brief letter to the editor (Epstein, 1964), approach the problem seriously until 1965, when, as a “side project,” I looked at the relationship between nuclear DNA content and cell volume in polyploid mammalian liver cells (Epstein, 1967; Epstein and Gatens, 1967). I was immediately struck by the beauty and simplicity of the relationship: over a large range of DNA content, cell volume is quite exactly proportional to ploidy. In 1967, I moved from the National Institutes of Health to the University of California, San Francisco, and in the course of this move switched my principal research focus from the genetic control of three-dimensional protein structure to the genetic control of very early mammalian embryonic development.