Each new issue of the Annual Review of Biochemistry was like a sorbet course during medical school: a palate cleanser between the stodgy mains of the curriculum. The dark blue books now fill three shelves in my study, beginning with volume 52 of 1983, the year I entered the University of Innsbruck.

I was a reluctant medical student, having bowed to paternal pressure. My father had grown up in the Soviet-occupied part of post-war Austria and, with financial support from his parish, been sent to a boarding school that specialized in the production of Catholic priests. At the age of 18 he struggled free of this destiny (which would have made my future existence precarious but not impossible, as some of his ordained classmates subsequently proved), but a continuing lack of funds put his wish to train as a physician out of reach. He became a half-hearted classicist instead, and the fulfilment of his medical dream fell to me. And so, when my time came to choose a course of study, my father, in what I suspect was a ploy to bend my nascent interests to his plan, arranged a visit with a colleague at the Technical University of Vienna. Seated in a dusty office, the professor of biochemistry reached for two aspirin tablets before explaining the cause of his headache: too many students; endless hours of tedious instruction; no time for research; and therefore no discoveries of significance by anyone at his institute, ever, with the possible exception of Hromatka’s procedure for making vinegar — “but that was probably an accident. Don’t come here; study medicine instead.” This performance sealed my fate until I, too, found the courage to shed an ill-fitting career, just as my father himself had done four decades earlier.

Among my favourite pieces in the Annual Review were the autobiographical chapters that open each volume. I remember reading that matchbook covers, not butterflies, were the dominant species in the Brooklyn streets of Arthur Kornberg’s childhood; that natural history and science were unfamiliar pursuits. Kornberg’s remark resonated because science was also outside the sphere of music, literature, and art inhabited by my parents; they appreciated science not as a source of beauty, pleasure or transcendence but as a base for practical advances. Only as a teenager, after a lengthy flirtation with writing fiction, did it dawn on me that science offered similar opportunities for creative expression: there was a possible world to be imagined. The need to check imagination against reality had given rise to an art form: the elegant experiment which arrived in a minimum of steps at a sharply stated inference. It was the mastery of this art that would later draw me to James Rothman.

Before then, however, I had to finish my degree — an increasingly unpleasant prospect as the course shifted to the clinic, just as I first tasted laboratory life with its refreshing mix of intellectual and manual work, of camaraderie and solitude. I eventually graduated but continued for years to freeze when the dean’s office called in the midst of an experiment, threatening to expel me if I didn’t pass dermatology at once, before realizing I had woken from a dream.

In his memoir for the Annual Review, Gottfried Schatz summed up university in 1950s Austria under the heading “Desert”. Little had changed a generation later. Scanning the arid plain of contented mediocrity for possible thesis advisors, I spotted a shimmering oasis (or was it a mirage?): Josef Patsch, recently repatriated from Baylor College of Medicine. My apprenticeship with him, studying lipid metabolism, gave me the first thrill of discovery, enough practice with a pen to accept Nabokov’s decree that writing requires “the precision of a poet and the imagination of a scientist”, and an idealized view of US academia as unlike anything I knew: international, risk-taking, and informal. Yet our bond — which bordered on friendship despite never losing the starch of “Herr Professor” — dissolved with my exodus to this Promised Land.

It was there, under Rothman’s influence, that my goals crystallized, albeit into an unexpected shape. Biochemistry had cast its spell on me with the rigour and inventiveness of its game, the audacity of breaking life into parts and understanding it by way of reassembly. Other branches of biology, especially neuroscience, were full of mesmerizing problems but lacked muscle by comparison. What would it take to apply the force of functional reconstitution to them? Could a neuroscientist isolate the electrical activity patterns that embody our experience like a biochemist purifies an enzyme, by fractionating them according to their power to evoke perception, action, emotion, or thought when added to a brain? But how could something like this ever be done — seizing control of many neurons while solving the needle-in-the-haystack problem of finding the right ones? One Saturday in June 1999, after my little daughter and I had crisscrossed New York Harbor on the Staten Island Ferry, as we sometimes did on weekends, an idea docked in my mind: visual photoreceptors, transplanted from their natural context, might be used for this purpose, as genetically encoded receivers of optical commands.

20 May 2021 Hong Kong