Marion Edmonds Smith (1926–2017)

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Marion Edmonds Smith (picture courtesy of Dr. Kendric Smith). Marion Edmonds Smith, Professor of Neurology (Research) at Stanford University, an internationally known pioneer in myelin neurochemistry, died on March 22, 2017 at the age of 90 in Los Gatos CA. She is survived by her husband Kendric Smith; they were married for 62 years. She is also survived by two daughters, Nancy Vincent (Vancouver WA) and Martha Silverman (Missoula MT) and five grandchildren. Marion was born on July 13, 1926 in Susanville, a small town in the California Sierra Nevada Mountains. She was very athletic growing up and enjoyed basketball, hiking, skiing and competitive swimming. She remained exceptionally fit her entire life, taking up Pacific Ocean windsurfing in her 60′s. Following in the footsteps of her grandfather, she attended the University of California at Berkeley where she received a Bachelor of Arts with honors in biochemistry in 1952, and a Ph.D. in 1956 in the laboratory of Dr. David Greenberg. Her thesis on the biosynthesis of proline was published in Nature (Smith, 1956). While in graduate school Marion met her husband Kendric Smith, who was also working on his Ph.D. in biochemistry. They married, and after graduation both obtained positions at the Stanford University School of Medicine, then located in San Francisco. When the Stanford Medical School moved to Stanford, Marion and Kendric moved to the campus where they raised two daughters. Marion rose to the rank of Professor at Stanford in 1974, and also held an appointment as Research Scientist at the Veterans Affairs (VA) Medical Center in Palo Alto. Marion was not only a productive neuroscientist, but enjoyed a rich family life with her husband Kendric and their two daughters. Their mountain cabin was her favorite retreat when writing grants and papers. She was an avid bird watcher and traveled with her husband around the world on birding trips. Marion played the piano, particularly enjoying classical music and ragtime jazz. She engaged in many activities, making pottery, camping, swimming and hiking. She was an excellent cook and accomplished skier, participating in NASTAR races at the Winter Conferences on Brain Research. After retiring, she was a docent at the Cantor Arts Center at Stanford, the Jasper Ridge Biological Station, and the Stanford Memorial Church. Marion published 110 papers altogether – original articles, reviews and book chapters – along with 70 abstracts for various meetings throughout the world. From her first paper in Nature in 1956 to her last review in 2001, she had a long, prolific, and creative career. Overall, Marion published four articles in the journal Nature, two as single author, one in Science, and all others in premier neurochemistry and cell biology journals. Few women of her time can boast such a pedigree with high impact factor journals. Marion published a third of her papers as single author, befitting a hard working investigator endowed with an independent spirit. She was a trailblazing neurochemist and scientist, a woman with boundless energy, can-do spirit and innovative ideas. She nevertheless had a collaborative spirit and co-authored with well-known investigators, to name just a few: Lysia Forno (Parkinson Lewy bodies), Lawrence Eng (co-discovered GFAP), Joyce Benjamins (myelin biochemistry), Jean de Vellis and Robert Skoff (oligodendrocyte glial biology), Nancy Sternberger (first myelin antibodies), Jaqueline Trotter (macrophages), Steven Waxman and Raymond Sobel (multiple sclerosis). Marion was very active at Stanford University and served on many academic committees. At Stanford, she was an outspoken force for equal treatment of women faculty, beginning with her membership on the Joint Committee for Status and Tenure of Women in 1972. Marion had visibility at both national and international levels. She served on several national scientific advisory boards and several editorial boards including Neurochemical Research (1981–1989) and the Journal of Neurochemistry (1981–1988). She was a member of study sections at the National Institutes of Health and the National Multiple Sclerosis Society and on VA Merit Review committees, recognition by peers of her expertise. She was well connected in the myelin community, scientifically aware of what people were doing and always willing to share her knowledge and expertise with others. In recognition of her research accomplishments, Marion received many honors including Phi Beta Kappa in 1952, Sigma Xi in 1955, Who's Who in American Women, but above all the prestigious 7-year Javits Neuroscience Award from the National Institutes of Health in 1988. Marion organized many symposia and workshops at international conferences, testifying to her leadership in several fields. Marion was admired and respected by her female and male peers alike. She is widely considered part of the core of women founders of neurochemistry in the early 1960s and 1970s. Marion was involved in scientific societies as well. Besides active membership in several societies, she sat on the board of Directors of the Winter Conference on Brain Research (requirements are excellent scientist and good skier). Notably, she was an enthusiastic founding member of the American Society for Neurochemistry (ASN) of which she served as Secretary then became the second woman President from 1991 to 1993. She was a role model for young neurochemists, both men and women, and she, along with Marjorie Lees (first ASN woman President) and Marian Kies (honored by the current ASN award for young investigators) were a myelin triumvirate. Marion remained an ASN Councilor, a testimony to her leadership, amicability, clarity of thinking and straightforwardness. Her 2000 review ‘Was the ASN a Myelin Society?’ is a detailed tally of abstracts across 30 years of conferences, and illustrates her fairness to set scores straight against criticism (Smith, 2000). Marion was very direct and not interested in petty politics, but was endowed with a great sense of humor. An excellent skier, she used to lure friends to the mountain tops at the Winter Conferences on Brain research, only to let them manage black diamond runs (recollection by Robert Skoff). Another anecdote recalls her helping Alex Chiu (then her graduate student) with injecting myelin basic protein when the rat kicked violently and Marion stabbed her finger, which swelled for days afterwards. Several of her Stanford colleagues came to her lab in Palo Alto to take her blood for study. Marion joked that she didn't know she was so popular among so many immunologists. Early on Marion steered toward clinically relevant research, with appointments at both the VA Neurology Service and the Stanford Department of Neurology. After her doctoral work on proline biosynthesis in 1956 (Smith, 1956), she had a successful post-doctorate at Stanford University with Dr. Henry Newman, a pioneer in studying alcohol metabolism. She found the rate-limiting step in ethanol metabolism was NADH reoxidation in the liver, resulting in two additional Nature papers. In 1961, with radioactivity being commonly used at the time to trace metabolism, she used 14C labeled ethanol and showed ethanol incorporation into fatty acids (Smith, 1961). The abrupt passing of Dr. Newman spurred Marion's transition from ethanol metabolism to myelin disorders. From that point on, Marion remained focused during her entire career on multiple sclerosis, which she investigated using many models of myelin perturbation, especially the inflammatory model experimental allergic encephalomyelitis (EAE). She was goal-driven, with the scientific insight to use her findings to change her research direction in innovative ways and move toward the next stage. Marion's logic was to focus initially on normal myelin lipid turnover, as one cannot understand a disease condition if one does not know the normal state. At the time, little was known about how myelin was generated. She first analyzed myelin lipid turnover and in 1963 published a preliminary study on the effect of fasting, since rats sick with EAE cannot feed themselves well (Smith, 1963). A perfectionist, Marion wanted to differentiate the effects of inflammation from fasting. The following year she explored myelin synthesis in EAE and discovered that, contrary to common belief, lipid turnover was increased in this inflammatory condition. From 1965 onward Marion set to decipher myelin metabolism in vitro, and in 1969 established an original approach for studying myelin membrane formation in brain and spinal cord slices (Smith, 1969) using the ‘tissue chopper’ developed by the British scientist Henry McIlwain (another stalwart of neurochemistry). Marion was hands on and remained active at the bench, endowed with a strong practical sense. Brain slice studies introduced by Marion were subsequently adopted as a useful tool by the glia community, since it circumvented the pitfalls of precursor accessibility hampered by blood-brain and cerebrospinal fluid barriers. Brain slices enabled analysis of complex myelination events across a relatively short period of 6–7 h, allowing pulse/chase studies with isotopically labeled precursors. It was appropriate for looking at the synthesis of myelin during the peak of myelination, as well as selecting specific brain areas. Marion made great strides in analysis of myelin metabolism, reporting that radioactive incorporation into lipids decreased markedly with development, suggesting it was directly proportional to myelin deposition. Marion pioneered studies of cholesterol metabolism in brain, and showed that the nervous system can biosynthesize much of the cholesterol, and that cholesterol is an important precursor for myelination (reviewed in Smith, 1987). In 1971, Marion extended her studies from lipid to protein turnover in myelin, and set out to compare central myelin to peripheral myelin (Rawlins and Smith, 1971). In 1972, she organized a round table on Myelin and Myelination at the annual ASN meeting, taking the lead on the topic to clear the perception that turnover of myelin proteins and lipids could last almost a year. Contemporary studies were performed with radioactive precursors of either lipids or proteins, with half-lives calculated over 200 days for both young and old animals, although measurements varied considerably depending on a myriad of variables. Marion made a breakthrough using careful analysis showing that myelin turnover was faster than generally assumed at the time. The results of her pioneering studies examining the turnover of myelin in vivo and in vitro were reviewed by her and Joyce Benjamins in a chapter of the first seminal book on Myelin edited by Pierre Morell (Benjamins and Smith, 1977). In their conclusion, the authors stated ‘Myelin is not the metabolically inert membrane it was once thought to be’. Having mapped normal myelin metabolism at both lipid and protein levels, Marion then launched a deeper investigation into mechanisms of myelin destruction. She explored more models of myelin perturbation such as triethyltin-induced demyelination in 1973, proteolytic degradation of myelin in 1974, and factors blocking electrical conduction in EAE, published in Science in 1975 (Seil et al., 1975). The international community was beginning to actively investigate mechanisms of demyelination as related to multiple sclerosis; at the time the field was relatively unexplored and the study of normal glial cell biology was still in its infancy. Highlighting this state of knowledge, Marion initiated at Winter Conferences on Brain research in 1973 a workshop on Mechanisms of Demyelination, and the following year in 1974 a workshop on Neurobiology of Glial Cells. Marion extended to the peripheral nervous system (PNS) (Rawlins and Smith, 1971) her studies of inflammation – experimental allergic neuritis, and proteolysis-driven in vitro demyelination. She organized a symposium on Peripheral Neuropathies at ASN in 1979, and a panel on Inflammatory Neuritis at Winter Conference on Brain Research in 1980. Her findings culminated in two book chapters in 1983 and 1984 on myelin metabolism in the PNS, neuritis and other peripheral neuropathies. She was widely recognized as an expert in myelin metabolism and its perturbations. It was time for Marion to move to the cellular level of myelin destruction and extend her investigations to the immunological side of multiple sclerosis. In 1983, Marion made a second breakthrough in collaboration with Lawrence Eng, who had recently isolated glial fibrillary acidic protein (GFAP) in multiple sclerosis plaques. They found that astrocyte proliferation and hypertrophy appeared early in EAE, simultaneously with the first inflammatory foci, and that GFAP was not confined to lesions but overexpressed in astrocytes throughout the brain (Smith et al., 1983). The fairly new technique of immunostaining with Eng's antiserum revealed a widespread GFAP increase in astrocytes, further quantified by radioactivity and immunoprecipitation. Marion was intrigued and continued investigating GFAP and astrocyte activation in connection with genesis of the astroglial scar in multiple sclerosis plaques. She was one of the first to investigate the role of other cells, besides myelin-producing oligodendrocytes, in the pathogenesis of inflammatory demyelination. Around that time, Naren Banik joined her laboratory (1974–1976), and worked on the degradation of myelin protein by protease in EAE which supported her hypothesis of protease-driven mechanism of demyelination (Banik and Smith 1977). In 1978, Marion began studying myelin proteolysis using lymphocytes from EAE, and in 1980 published a book chapter entitled ‘Protease inhibitors and the suppression of EAE’ (Smith, 1980). She clearly understood the potential therapeutic relevance of her investigations and was already doing translational research. Marion focused early on the role of macrophages in demyelination. She reported that myelin antibodies increased uptake (opsonization) and metabolism of CNS myelin by cultured macrophages in 1986 in collaboration with Jacqueline Trotter (Trotter et al., 1986), and published in 1990 similar effects for PNS myelin with Joyce Benjamins (Smith et al., 1990). Marion subsequently assessed the role of cerebrospinal fluid from EAE animals in myelin phagocytosis by macrophages. In 1991 Marion extended her studies of myelin phagocytosis to microglia, the only CNS cells endowed with phagocytic properties, which clearly fascinated Marion. At her favorite conferences – ASN, Winter Conferences on Brain Research and International Society for Neurochemistry – Marion organized a symposium on Biochemistry of Microglia in 1991, a panel on Microglia: New Roles in 1992, followed by a workshop on Microglia in 1993. Marion sat on the National Multiple Sclerosis Society Advisory Committee on Fundamental Research from 1982 to 1996, virtually until retirement. She remained intent throughout her career to study demyelination, focusing on cells of the innate immune system, macrophages and microglia, true to her neurobiology roots. Her last paper (Smith, 2001) was a review on microglia. Marion was creative and energetic, enthusiastic about her research and always supportive of younger scientists. Her former graduate student Alex Chiu wrote in a 1996 issue of Neurochemical Research honoring Marion (Chiu, 1996): ‘For the lucky ones who know Marion well, her warmth, knowledge and integrity complete a persona that is close to the ideal scientist.’ Authors have no conflict of interest.