Mark A. Smith: neurocytochemistry innovator

Mark A. Smith Neurochemistry lost a luminary in December. In less than 20 years, Mark Smith transformed the neuroscience of oxidative stress from anecdotal phenomena to a cohesive platform on which to build common mechanisms of physiology and pathology. It seems difficult to recall now, but the same could not be said when Mark began his career in Alzheimer disease research. He fundamentally revolutionized our understanding from poorly defined changes in lipofuscin, insolubility, and bulk oxidative modification to a program of events scripted throughout life. Oxidative stress was transformed from the rusting nail to a well-honed homeostatic mechanism, applicable to human disease and indeed the human brain. Mark led this transformation by an elegant and yet very simple approach, understanding that physiology/pathology occurs at the subcellular level. At the time, oxidative stress studies were led by chemists with sophisticated techniques, but applied to whole brain homogenates that in most cases diluted cellular context. So while neurons undergo increased oxidative damage, Mark knew that bulk analysis would trivialize the findings at the organelle level because of changes, for example, in basement membranes of large blood vessels that accumulate changes throughout life due to low turnover, whereas changes in macromolecules as a function of their subcellular compartment would similarly go entirely undetected. Mark’s first contribution was the development of neurocytochemical probes to define oxidative modifications, metal changes, antioxidant responses (enzymes, cofactors, and signal transduction), redox reactions, mitochondria, apoptotic pathways, cell cycle reentry, and the list goes on. If it could inform, Mark developed the probe. Legacy of this transformation continues when the limitations of studies referred to above are examined alongside Mark’s studies. He understood as well as anyone the cooperative arrangement of brain cells that needed to be resolved, both in isolation and as a functional unit. Mark placed all into an experimentally defined context, transforming our understanding and providing a platform for numerous future studies. And it was all performed so elegantly and naturally, with humor and humility that came to define him as a person, that even many close to him were so blinded by Mark Smith the man, they missed how thoroughly he transformed our field. Like his gifts to the field, his own gift was elegant in its simplicity: he combined his training as a neurochemist and cellular pathologist, a combination not previously applied to oxidation. As a student of science, Mark remembered the renaissance of cytology that spawned the work of Ramon y Cajal, Nissl, and Alzheimer and applied the chemistry of oxidative stress to develop families of cytological approaches that are now in wide use (Sayre et al. 1999). And he only began there, using insights from his careful descriptions to define first a novel view of oxidative stress in Alzheimer disease as a well regulated homeostatic state that plays a protective function and later to extend these thoughts to amyloid-β (Joseph et al. 2001). It is later where Mark’s gift as communicator in written and spoken word created the first questioning of the amyloid cascade hypothesis (Perry et al. 2000). Mark’s studies are among the most cited in oxidative stress and Alzheimer disease research (http://sciencewatch.com/ana/st/alz2/authors/ and http://www.freeradicalscience.com/labs.php). In addition, he won numerous awards including the Jordi-Folch award from the American Neurochemistry Society, Hermann-Esterbauer Award from the HNE Society, the Outstanding Investigator Award from the American Society for Investigative Pathology, Denham Harman Research Award from the American Aging Association, and the Goudie Lecture and Medal from the Pathological Society of Great Britain and Ireland. He was a fellow of the American Association for the Advancement of Science, American Aging Association, Royal Society of Medicine, and the Royal College of Pathologists. Those close to Mark were enriched by his presence; his friendly demeanor, his loud baritone voice that still rings in the mind, and his naked openness to all aspects of life, among many other attributes. But most of all, it is his generosity that will be missed. Mark was always there to assist students, colleagues, mentors, and acquaintances, freely giving of himself in every possible way, with all that he had in insights, counsel, reagents, and the commodity he eventually had too little of, time. Literally scores have come forward with how Mark touched their lives, not just by the creditability of his science but by the virtue of a life well lived, with generosity to those around him (http://www.j-alz.com/marksmith.html).