Mark A. Smith: The Scientist, the Man

Abstract

Alzheimer disease (AD) research suffered a devastating loss with the death of Mark A. Smith on 19 December 2010. In addition to being the most prolific and fifth most cited AD author, Mark had a keen eye for innovation and quality of execution. Investigations into oxidative stress, cell cycle reentry, gonadotropins, mitochondria, metal homoeostasis and other novel ideas owe much of their origin and all of their continued influence to Mark’s unparalleled energy, as well as a progressiveness and generosity that enabled him to share his intellectual achievements and promote his colleagues and trainees. Mark was initially drawn to oxidative stress as a means of understanding the biology of AD and the necessity, in his view, of maintaining a fidelity to evolutionary adaptation for successful ageing. So at a time, when virtually all others were embracing classical notions of gain-of-function toxicity, Mark brought oxidative stress to the forefront with his first studies, one demonstrating glycation and another induction of heme oxygenase 1, in human AD in vivo. As a result, investigation into oxidative stress comprises 5% of the total AD research output and has continued to rise; something that was inconceivable only 20 years ago. In a short period of time, Mark became convinced that oxidation must be part of a programme of changes that surface at the initiation of AD if not sooner. Further demonstrating cell cycle reentry in neurons at risk of death in AD was the first success of his thought process, leading to the ‘two-hit’ hypothesis, in which he proposed that oxidative stress as well as cell cycle conspire to initiate non-apoptotic cell death. As data began to accumulate that the amyloid cascade hypothesis was fundamentally upside down, and the neuroscience community, in the quiet of private reflection, began to see the need for a paradigm shift, Mark’s call for objectivity, both in the literature and with his booming baritone voice in lectures all over the world, was a welcome instillation of courage and inspiration. Perhaps more than Mark realized, he was a voice of strength and scientific values that were badly needed in the face of a peer review system and granting agencies that, in Mark’s words, was caught in a game of ‘follow the leader’. In essence, by questioning the amyloid cascade hypothesis, Mark ushered the return of scientific values, the necessity for objectivity and the necessity to always question, for numerous colleagues thirsting for such a return. Yet questioning the amyloid cascade hypothesis was also a natural continuation of his efforts, and the extension of his experimental evidence and intuition. The notoriety of numerous debates, including the last this past October (Controversies in Neurology, Barcelona, Spain, October 2010), and over a decade of articles claiming analogy to protective responses were simply a continuation of Mark’s inclination towards objective appraisal of the evidence at hand. INTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY Int. J. Exp. Path. (2011), 92, 297–298