Mark Anthony Smith, PhD, was born in Leicester, UK, on August 15, 1965. The proud son of a coal miner, Mark grew up as a witness to hard work and sacrifice, and would carry himself throughout life with the appeal of a humble and virtuous upbringing.
Mark was the first in his family to attend college, after receiving a scholarship to Durham University. Not given to idleness, Mark was active in collegiate football (soccer), where he earned the nickname ‘Animal’, a tribute to his tireless style of play. In 1986, he received a BSc degree with Honors in biochemistry and molecular biology. He then matriculated at Nottingham University and obtained a PhD in biochemistry in 1990 under Michael Landon.
After a brief immersion in big pharma as a postdoctoral biochemist under Carolyn A Foster in the Division of Immunodermatology at Sandoz Forschungsinstitut (now Novartis) in Vienna, Austria, Mark sought and obtained a position as Research Associate in 1992, under the guidance and mentorship of Dr George Perry, at Case Western Reserve University (OH, USA), beginning in earnest his trajectory in neuroscience and Alzheimer’s disease research.
Mark’s initial scientific work focused on oxidative stress. While previously a nebulous concept better reserved for highly artificial experimental environments, Mark brought the focus into the mainstream by direct application to the human brain. He identified and characterized in situ a spectrum of oxidative stress adducts, such as nitrosylation, lipid peroxidation and advanced glycation adducts, among others. In pursuit of one of his ‘cunning ideas’, using an elegant application of Prussian blue and diaminobenzidine to brain tissue in the presence of hydrogen peroxide, Mark was the first to demonstrate the cellular distribution of redox-active iron in the Alzheimer’s disease brain. Mark was also the first to crystallize the role of cell cycle activation as a basic mechanism of cellular pathophysiology within the brain. In each area, Mark stimulated interest within the scientific community, and an enormous body of literature invariably followed.
As a collaborator, Mark knew no limits. He had the gift of seeing the ‘big picture’ and viewed science, not as a set of facts awaiting elucidation, but as a set of constantly evolving concepts. Ever aware that the dogma of today will prove primitive and erroneous tomorrow, no collaboration was turned away, no new hypothesis was dismissed and every idea was deemed ‘brilliant!!’
Mark’s broad and encompassing view of neurobiology, and fierce fidelity to the objective interpretation of data, ran counter to the amyloid cascade, which he viewed as reductionist and a conclusion in search of data. The academic debate that ensued was as natural as it was inevitable, with leading authority, abundant funding and entrenched schools of thought on the one hand, and Mark’s fearlessness, straight-away manner and utter pleasure in a healthy debate on the other. In regular lectures all over the world, with a booming voice and insightful style, Mark threw down the gauntlet again and again to the neuroscience community, challenging it to re-examine its own data. Thus comprised what may be Mark’s transcendent accomplishment. Through his unparalleled energy, collaborative abilities and gift of communication, there has indeed been a discernible paradigm shift in Alzheimer’s disease pathobiology, while the phrase ‘Mark was right’ is increasingly heard in private and sometimes even in public, among other leading authorities.
As testimony to Mark’s contributions to science, he served as Editor-in-Chief of the Journal of Alzheimer’s Disease, and also sat on the Editorial Board of a dizzying number of leading journals, including Science Translational Medicine, Discovery Medicine, Journal of Neurochemistry, Journal of Pathology, Journal of Neuropathology and Experimental Neurology, The American Journal of Pathology and Expert Review of Neurotherapeutics. With an h-index of 73 and over 800 peer-review articles and reviews that have received over 21,000 citations, he was named as one of the top Alzheimer’s disease researchers in the world, one of the top 100 most-cited scientists in neuroscience and behavior, and one of the top 25 scientists in free radical research. All of this Mark accomplished by the age of 45. He was also the most prolific and most cited faculty member on campus (across all schools) at Case Western Reserve University, where his work alone accounted for more than 1% of the publications and 4% of the citations, in a recent survey. Mark achieved full professor with tenure at the age of just 36. While no detailed records of faculty ages as a function of rank and tenure are available, he is clearly among the youngest, if not the youngest, in the history of Case to achieve this distinction.
His many honors included the Jordi Folch-Pi Award from the American Society for Neurochemistry, the ASIP Outstanding Investigator Award from the American Society for Investigative Pathology and the Denham Harman Research Award. He was elected as Fellow of the Royal College of Pathologists, Fellow of the American Aging Association and a Fellow of the American Association for the Advancement of Science (the world’s largest scientific organization). He had recently been awarded the Goudie Lecture and Medal of the Pathological Society, but passed away before he could deliver the lecture.
Mark’s promise for continued progress in science will be sorely missed by humankind, but the loss of Mark Smith, the man, cannot be measured. Among his qualities that are impossible to sum, Mark had a side-splitting wit, a magnetic personality and a disarming ear-to-ear grin. He greeted everyone as though it was his privilege to see them, always with a smile, an earnest enthusiasm and a laudatory phrase that set a tone of friendliness and levity. His energy and love of life were palpable, and extended well beyond the workplace. In a sense, the world was his laboratory, and every fellow human being his collaborator.
While out of the lab, Mark had the hobby of purchasing old houses, fixing them up and renting them out. Where he found the time is among the many mysteries. He also had a hobby in old European automobiles, which were constantly breaking down, and required his continuous tinkering. Mark’s love of soccer also continued throughout his life, as he was active in soccer leagues and played at a high level until the time of his death. During the World Cup competition, the laboratory would take a back seat, and he and friends would sit, often at a local pub, glued to the satellite feed, shouting encouragement over mugs of English beer. Coaching his two boys and playing soccer with them in his back yard was a more recent pastime, among the many that came to a close far too soon.
Mark leaves behind a beautiful wife and the love of his life in Gemma Casadesus, an accomplished behavioral neurobiologist and rising star in her own right, whose courage and fortitude in the aftermath of Mark’s loss was, and is, an inspiration to everyone. His son William, 7 years old, shares Mark’s enthusiasm for life and inherited his father’s magnetic smirk and sidelong glances, along with the thoughtful, deliberate qualities of his mother, and the intelligence of both. His son Luke, who turned 6 years of age on Christmas day, ever at papa’s side while he tinkered in the yard or in the garage, is so like Mark in appearance and mannerism, there can be little doubt that Mark is alive and well. Mark’s father John (Jack), now in his 70s and retired to Spain, would occupy his ‘down time’ during visits with Mark and Gemma, by rebuilding entire sections of their house. In a moment’s interaction with Jack, with his bright, purposeful eyes, straightforward manner and baritone voice, Mark’s heritage becomes immediately clear. Mark is also survived by his older sister Tina (Wakeling) of the UK. His mother, Rita, who always maintained that Mark “is a good lad”, passed away in 2004.
It is of little consolation to those closest to Mark that he would occasionally comment on the circle of life and the unlikelihood of his reaching old age. Whether he sensed something in time and space that inspired him to live every day as though it were his last, or whether losing his life 95 years to the day after Alois Alzheimer passed away is evidence of some larger celestial plan, will remain unanswered questions. The certainties we are left with are Mark’s footprints in the annals of science, which will only grow over time; the fact that Mark’s contributions to science, while timeless and virtually without parallel, still pale in comparison to Mark Smith the man; and the fact that no language of mortal existence could ever provide proper summation, nor describe the depth and span of the incredulousness and void, at the passing of such an embodiment of life, and now the legend that is Mark A Smith, into the Hereafter.
Yet we are sustained, somehow, by Mark himself, by memory images of an enthusiasm for life so vivid and clear, that it is simply not possible to think of him in the past tense alone. A thought of the past brings a smile to the present and a purpose for the future. Such will be his legacy above all others, for many years to come.
Written by RJ Castellani, MD (Friend and collaborator)
University of Maryland, MD, USA