Journal of the History of the Neurosciences Basic and Clinical Perspectives

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Theodore L. Sourkes PhD, FRSC, OC (February 21, 1919–January 17, 2015) Paul Foley To cite this article: Paul Foley (2016): Theodore L. Sourkes PhD, FRSC, OC (February 21, 1919–January 17, 2015), Journal of the History of the Neurosciences, DOI: 10.1080/0964704X.2015.1114172 To link to this article: http://dx.doi.org/10.1080/0964704X.2015.1114172

Published online: 29 Feb 2016.

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JOURNAL OF THE HISTORY OF THE NEUROSCIENCES http://dx.doi.org/10.1080/0964704X.2015.1114172

OBITUARY

Theodore L. Sourkes PhD, FRSC, OC (February 21, 1919– January 17, 2015) Paul Foley

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Neuroscience Research Australia, Sydney, Australia

I first met Ted Sourkes in Haifa in 1998, during research for my thesis on the history of antiparkinsonian therapy. Ted was one of the major participants in the L-DOPA story. Together with his collaborator in the early 1960s, neurologist André Barbeau, and his graduate student, Gerard Murphy, he had reported in 1961 that the dopamine concentration in urine was lower in parkinsonian patients than in a control group (Barbeau, Murphy, & Sourkes, 1961). This motivated their investigation of the effects of oral L-DOPA administered to patients with parkinsonism at about the same time that Oleh Hornykiewicz and Walter Birkmayer were examining L-DOPA therapy in Vienna. The results of treatment were promising, but interpretation of their study of urinary dopamine was complex, at least in retrospect; that is, the experimental basis for the Montréal trials of L-DOPA was dubious. It was, therefore, with trepidation that I broached the subject with Ted, but he simply smiled when I asked him about it and assured me that my question was fully justified; he and Barbeau had perhaps made the right decision for a flawed reason, but this meant only that the L-DOPA trial was ultimately the more important experiment. The calm and friendly response — without him mentioning that I was unaware that he had previously discussed in print some of the problems I had “discovered” — characterized all my subsequent interactions with Ted Sourkes. These were too infrequently face-to-face (during meetings in Canada), but he was consistently supportive of my historical research, providing me with many documents to which I would otherwise have had no access. He was the epitome of the gentleman scholar: Every conversation I shared with him was both a personal and an intellectual pleasure. Theodore Lionel Sourkes (Figure 1) was born on February 21, 1919 in Montréal, the second son of Isadore and Fanny Sourkes (née Golt). Aside from brief periods elsewhere, Montréal would remain his home and the focus of his life. His interest in science had been piqued during his high school years, when he also became aware of the “power of theory,” underpinned by careful analysis, to understanding and changing the world. After completing his high school studies in Québec City, where he excelled in both Latin and mathematics, he surprised many by his choice in 1935 to study biochemistry at McGill University; he had not been expected to do something that seemed so “applied.” The biochemistry department was at this time led by the prominent pituitary researcher James Bertram Collip, the first biochemist to purify insulin. After completing his Bachelor’s degree at McGill in 1939, Sourkes was prevented by financial constraints from proceeding directly to a doctorate, so he spent a series of short periods in the laboratories of the Food CONTACT Paul Foley NSW 2031, Australia. © 2016 Taylor & Francis

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Neuroscience Research Australia, Barker Street, Randwick, Sydney,

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Figure 1. Theodore L. Sourkes, PhD, FRSC, OC. Image provided courtesy of the Osler Library of the History of Medicine, McGill University, Montréal.

and Drug Directorate in Ottawa, Queen’s University in Kingston (Ontario), and the Frank W. Horner pharmaceutical company in Montréal. Poor vision prevented Ted from enlisting in the armed forces during the Second World War, but he was able to contribute to the Canadian war effort through his work at a chemical engineering factory producing armaments in Toronto. It was during this period that he met and fell in love with Shena Rosenblatt, then a trainee anesthesiologist. The pair married in 1943, and anyone who met the couple in the ensuing seven decades will attest to their deep and enduring love for one another. They would have three daughters, one of whom (Doreen) died as an infant. In 1945, Ted finally commenced his Master’s degree in science in the departments of Animal Nutrition and Chemistry at McGill University, working on the nutritional properties of proteins with Earle Wilcox Crampton, Canada’s most distinguished nutritional scientist. After graduating magna cum laude, he moved in 1946 to Cornell University (Ithaca, New York), in May 1948 completing his doctoral research (an investigation of transmethylation) under the supervision of James Sumner, the 1946 Nobel Prize laureate for chemistry. After a sojourn teaching biochemistry at Georgetown University in Washington, DC, Sourkes was invited to join the Merck Institute for Therapeutic Research (Rahway, New Jersey) in 1949, where he was initially concerned with metabolism in the adrenal medulla. After important investigations of the specificity of the adrenal decarboxylases, Sourkes was entrusted with testing a series of novel substances designed to block DOPA decarboxylase (aromatic L-amino acid decarboxylase). Merck was seeking a drug that reduced essential hypertension by hindering noradrenaline synthesis, and, at this point, DOPA decarboxylase was the only identified enzyme in this pathway. A panel of methylated α-amino acids had been synthesized for this purpose, and Sourkes’ major achievement was the detailed exploration of one of these compounds, α-methyl-DOPA, which subsequently became the prototype antidecarboxylase. By 1958, its antihypertensive properties had been demonstrated in animals and humans, and the drug became famous as “methyldopa” (Aldomet), still included in the Essential Medicines catalogue of the World Health Organization. In 1953, Sourkes was invited to join the Allan Memorial Institute of Psychiatry at McGill University as senior research biochemist because of his interest in the biochemical bases of

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mental disease, and he remained here until his retirement. He established a neurochemistry laboratory in which he further pursued his investigations of α-methylated amino acids and DOPA decarboxylase, while his first graduate student John Lagnado initiated monoamine oxidase research; both these enzymes would later be first purified in Sourkes’ laboratory. At the end of 1955, Sourkes’ group was measuring catecholamines in various tissues, research facilitated in 1959 by a special equipment grant that allowed him to acquire a spectrofluorophotometer, enabling him to adopt the latest fluorometric detection methods, then available to few laboratories. Collaboration with clinicians also commenced at about this time, as his research interests focused on the biochemical basis of psychiatric disease, a theme explored at length in his landmark 1962 monograph, Biochemistry of Mental Disease. Among other topics, he was also interested in endocrine changes in depression and explored the use of catecholamines for treating insulin-induced schizophrenia and of α-methyldopa for certain schizophrenia types and Huntington’s chorea. Towards the end of the 1950s, Sourkes was moved by recent publications on the localization of brain monoamines to focus his attention on the biochemistry of basal ganglia disorders. In 1957/1958, Swedish pharmacologist Arvid Carlsson had provided evidence that indicated that dopamine was probably involved in basal ganglia function. Sourkes’ familiarity with α-methyl-DOPA placed him in an excellent position to commence investigations of L-DOPA metabolism. This research interest also led Sourkes to take up contact with a young neurologist at the University of Chicago, André Barbeau, with whom a fruitful if brief partnership would develop after Barbeau transferred to the Montréal Neurological Institute at the beginning of 1960. In 1961, Sourkes published a review of the role of dopamine in basal ganglia disease, including his finding that it was possible to elevate or depress brain dopamine levels with either L-DOPA or α-methyl-DOPA, leading him to ponder the implications for the treatment of parkinsonism. This was followed by their report in Science by Barbeau, Murphy, and Sourkes (1961) that the urinary excretion of dopamine (but not of noradrenaline or adrenaline) was significantly reduced in parkinsonian patients. The Montréal report would long be cited alongside that of Ehringer and Hornykiewicz (1960) as evidence of the dopamine deficiency in Parkinson disease, and, like the Viennese report, motivated trials of oral L-DOPA therapy. Sourkes prepared the capsules given by Barbeau to a total of 26 patients; the alleviation of akinesia and rigidity seemed promising, but the trials were brought to a halt by the expense of the then scarce amino acid. At this point, Sourkes switched to an alternative research direction that proved equally significant: neurophysiological investigations which established that a nigrostriatal nervous pathway (the existence of which was then not generally recognized) was central to the role of dopamine in basal ganglia function. This research was undertaken in collaboration with neuroanatomist and experimental neurologist Louis J. Poirier (initially in Montréal, and later at the Université Laval, Québec City). In May 1963, Sourkes and Poirier began a collaboration that aimed to draw together experimental neurophysiological findings and neurochemical data to produce a monkey model of parkinsonism that reproduced more accurately the symptoms of the human disorder than had any earlier attempts. The first of a series of major publications, in Brain in 1965, indicated that the pars compacta of the substantia nigra normally exerts a direct influence on striatal catecholamine concentrations. Further investigation of the monkey model clearly established the central role played by dopamine in parkinsonian tremor; further, the measured decline in striatal concentrations

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of the major dopamine metabolite, homovanillic acid (HVA), corresponded with changes identified by Hornykiewicz and his group in the parkinsonian brain. But one of the most important concepts that emerged from the Sourkes’ and Poirier’s work was the realization that changes in several monoamines were required to produce “parkinsonian” symptoms; the idea that the disorder could be seen as a simple deficiency in one substance or the interruption of a single pathway was thus rendered unlikely. The importance of this work for neurochemistry in general cannot be overestimated; Poirier and Sourkes later commented (when this paper was cited as a “citation classic” by Current Contents; see Poirier & Sourkes, 1980) that these studies “stimulated studies aimed at the identification of neurochemically defined pathways and their role in behavioral and psychoneuroendocrinological phenomena.” It is easy to forget that the idea of transmitterdefined pathways was unusual in 1964; neural tracts were defined by histological techniques according to reactions that did not reflect transmitter content. Some residual suspicion persisted regarding Sourkes’ and Poirier’s findings, as the integration of experimental neuroanatomy, neurochemistry, and behavioral studies was a novelty, and detecting the nigrostriatal pathway was clearly anything but classic histology. These doubts were soon allayed by functional investigations and by the application of new techniques in Sweden that permitted visualization of the pathway. The first unequivocal demonstration of a unity between physical lesion, neurochemical changes, and behavioral abnormalities was a major step forward in establishing neurochemical investigations as the dominant research paradigm in the further investigation of neurological disease. While Ted Sourkes, biochemist and neuropsychopharmacologist, is perhaps most closely associated with the investigation of the metabolism and functions of central and peripheral catecholamines, he also had a long-time interest in the metabolism of the amino acids tryptophan, histidine, and ornithine, and particularly in the roles played by another monoamine, serotonin. In 1955, for instance, he reported that α-methyl-tryptophan induces tryptophan catabolism (Sourkes & Townsend, 1955). In 1988, he returned to the idea and suggested that α-methyl-tryptophan, as the precursor of α-methyl-serotonin, could be used both in the assessment of serotonin synthesis in the living brain and to supplement serotonergic transmission in conditions where it is deficient (see, for example, Missala & Sourkes, 1988; Diksic et al., 1990). In the early 1970s, he published a series of papers that helped define the advantages and limitations of measuring biogenic amine metabolites in cerebrospinal fluid as an indication of the metabolism of the parent amines in the brain (for example, Garelis & Sourkes, 1973; Garelis et al., 1974). From 1965 to 1991, Ted Sourkes was Director of the Neurochemistry Laboratory in the McGill Department of Psychiatry. He was an enthusiastic and popular teacher and research leader, and his rigorous but sympathetic approach to each responsibility are often mentioned by those who have experienced him, as is his genuine personal warmth and his gentle sense of humor. Between 1949 and 2010, he published over 300 journal articles and book chapters covering a range of topics, but typically linked with clinical brain disorders, particularly of the basal ganglia. This significant scientific oeuvre has been repeatedly recognized by his peers and by his country. He was elected to the Royal Society of Canada (Société Royale du Canada) in 1971 and was appointed an Officer of the Order of Canada in 1993; in 1982, he received the inaugural Prix Heinz-Lehmann of the Canadian College of Neuropsychopharmacology (CCNP) for outstanding contributions to Canadian neuropsychopharmacology, in 1990 the CCNP Medal, and in 1998 the Prix

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Wilder-Penfield, awarded by the government of Quebec for contributions to the biomedical sciences. Further, he received the Order Andres Bello of the Government of Venezuela in 1987, received an honorary doctorate from the University of Ottawa in 1990 and was twice awarded the senior award of the Parkinson’s Disease Foundation (1963, 1966). Several seminars have been held in his honor over the years, including those held by the CCNP (1988), the International Society for Neurochemistry (1989), and the International Symposium on Parkinson’s Disease (1998). In 2013, McGill University inaugurated the Theodore L. Sourkes Lecture Series in Neuropharmacology as a tribute to his scientific legacy; the Department of Pharmacology and Therapeutics awards the annual Theodore Sourkes Prize for the best article on pharmacology by a student. Readers of this journal will also be familiar with another aspect of Ted Sourkes’ career, his intensive engagement with the history of science, particularly of biochemistry, in which endeavor he stands in line with Donald Tower and Henry McIlwain. Some assume that this interest developed after his retirement, but his first historical article, on the German physiological chemist Moritz Traube (1826–1894), appeared in 1955, and his 1967 volume on Nobel Prize Winners in Medicine and Physiology attracted widespread acclaim. But his activities in this area certainly increased after his retirement, with highlights including his small volume on the life and career of pioneer biochemist Johann Thudichum and his series of papers on the history of the chemistry of the brain, particularly in France. These publications were not the work of a dilettante but rather exhibited the same precision, freshness, and originality of ideas that he had demonstrated in his laboratory research. He explored the processes by which discoveries in the neurosciences have been made, and the historical contexts in which they were embedded, but did not neglect the key and indispensable roles played by individuals in these developments; his own career taught that science is by no means a dispassionate process inured to the influence of human foibles. The excellence of his contributions in this area was recognized in 2009 by the award of the Lifetime Achievement Award of the International Society for the History of the Neurosciences; he had previously won (2001) their award for Outstanding Article in the History of Neurosciences for “An Element of Thought: Phosphorus and Mental Philosophy in the Nineteenth Century” (Sourkes, 1998). His last major publication on any subject was the chapter on “the discovery of neurotransmitters, and applications to neurology” he contributed to the history volume of the Handbook of Clinical Neurology in 2010. Sourkes died from pneumonia on January 17, 2015 at the Montreal General Hospital, and his erudition and his company will be missed by all those who enjoyed the honor of calling him a friend or colleague. Ted is survived by his beloved wife Shena Rosenblatt, their two daughters Barbara, a clinical psychologist, and Myra Sourkes, a neurologist, and three grandchildren.

Key publications by Theodore L. Sourkes mentioned in this article (with his five most-cited papers marked in brackets) Barbeau A, Murphy GF, Sourkes TL (1961): Excretion of dopamine in diseases of basal ganglia. Science 133: 1706–1707. Diksic M, Nagahiro S, Sourkes TL, Yamamoto, YL (1991): A new method to measure brain serotonin synthesis in vivo. I. Theory and basic data for a biological model. Journal of Cerebral Blood Flow and Metabolism 10: 1–12.

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Garelis E, Sourkes TL (1973): Sites of origin in central nervous system of monoamine metabolites measured in human cerebrospinal-fluid. Journal of Neurology, Neurosurgery, and Psychiatry 36: 625–629. Garelis E, Young SN, Lal S, Sourkes TL (1974): Monoamine metabolites in lumbar CSF: The question of their origin in relation to clinical studies. Brain Research 79: 1–8. [Ranked fifth most-cited paper] Lal S, Delavega CE, Sourkes TL, Friesen HG (1973): Effect of apomorphine on growth-hormone, prolactin, luteinizing-hormone and follicle-stimulating hormone levels in human-serum. Journal of Clinical Endocrinology and Metabolism 37: 719–724. [Ranked fourth most-cited paper] Missala K, Sourkes TL (1988): Functional cerebral activity of an analogue of serotonin formed in situ. Neurochemistry International 12: 209–214. Poirier LJ, Sourkes TL (1965): Influence of the substantia nigra on the catecholamine content of the striatum. Brain 88: 181–192. [Ranked first most-cited paper] Poirier LJ, Sourkes TL (1980): Citation classic: Influence of substantia nigra on catecholamine content of striatum. Current Contents: Life Sciences 296 (34, 14). Retrieved from http://garfield. library.upenn.edu/classics1980/A1980KD04800001.pdf. Poirier LJ, Sourkes TL, Bouvier G, Boucher R, Carabin S (1966): Striatal amines, experimental tremor and the effect of harmaline in the monkey. Brain 89: 37–52. [Ranked third most-cited paper] Sourkes TL (1949): Transmethylation of guanidoacetic acid in beef liver autolyzates. Archives of Biochemistry 21: 265–272. Sourkes TL (1954): Inhibition of dihydroxyphenylalanine decarboxylase by derivatives of phenylalanine. Archives of Biochemistry and Biophysics 51: 444–456. [Ranked second most-cited paper] Sourkes TL (1961): Formation of dopamine in vivo: Relation to the function of the basal ganglia. Revue Canadienne de Biologie 20: 187–196. Sourkes TL (1962): Biochemistry of Mental Disease. New York, Hoeber Medical Division, Harper & Row. Sourkes TL, Poirier LJ (1966): Neurochemical bases of tremor and other disorders of movement. Canadian Medical Association Journal 94: 53–60. Sourkes TL, Rodriguez HR (1967): α-Methyldopa and other decarboxylase inhibitors. In: Schlittler E, ed., Antihypertensive Agents, Medicinal Chemistry Series. New York, Academic Press, Vol. 7, pp. 151–189. Sourkes TL, Townsend E (1955): Effects of α-methyl-DL-tryptophan on the oxidation of tryptophan. Canadian Journal of Biochemistry and Physiology 33: 735–740.

Sourkes' major articles on neuroscience history Jasper HH, Sourkes TL (1983): Nobel laureates in neuroscience: 1904–1981. Annual Review of Neuroscience 6: 1–42. Sourkes TL (1955): Moritz Traube, 1826–1894: His contribution to biochemistry. Journal of the History of Medicine and Allied Sciences 10: 379–391. Sourkes TL (1970): 25 years of biochemical psychiatry. Canadian Psychiatric Association Journal 15: 625–629. Sourkes TL (1976): The neurochemical work of Hans Weil-Malherbe. Neuropharmocology 15: 443–448. Sourkes TL (1988): In memoriam: Juda Hirsch Quastel 1899–1987. Journal of Neurochemistry 50: 1325–1326. Sourkes TL (1990): Reflections at seventy. Journal of Neural Transmission Suppl. 29: 5–12. Sourkes TL (1991): Early clinical neurochemistry of CNS-active drugs. Bromides. Molecular and Chemical Neuropathology 14: 131–142. Sourkes TL (1992a): Meningitis in the 1860s. Canadian Medical Association Journal 146: 1153. Sourkes TL (1992b): The origins of neurochemistry: The chemical study of the brain in France at the end of the eighteenth century. Journal of the History of Medicine and Allied Sciences 47: 322–339. Sourkes TL (1992c): Early clinical neurochemistry of CNS-active drugs. Chloral hydrate. Molecular and Chemical Neuropathology 17: 21–30. Sourkes TL (1993a): Thudichum’s “Chemistry of the Brain” a century later. Journal of Psychiatry and Neuroscience 18: 51–53.

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Sourkes TL (1993b): John Simon, Robert Lowe, and the origin of state-supported biomedical-research in 19th-century England. Journal of the History of Medicine and Allied Sciences 48: 436–453. Sourkes TL (1993c): How Thudichum came to study the brain. Journal of the History of the Neurosciences 2: 107–119. Sourkes TL (1995a): The protagon phoenix. Journal of the History of the Neurosciences 4: 37–62. Sourkes TL (1995b): Seventeenth- and eighteenth-century commentators on the chemical composition of the brain. Journal of the History of the Neurosciences 4: 204–215. Sourkes TL (1996): Light and enlightenment: Cabanis, ideology, and the role of phosphorus in the brain. Journal of the History of the Neurosciences 5: 254–264. Sourkes TL (1997): Newborn infants with yellow brains: The discovery of kernicterus in Germany, 1875–1908. Journal of the History of the Neurosciences 6: 325–330. Sourkes TL (1998): An element of thought: Phosphorus and mental philosophy in the nineteenth century. Journal of the History of the Neurosciences 7: 108–124. Sourkes TL (1999): Discoveries in the human brain: Neuroscience prehistory, brain structure, and function. Journal of Psychiatry and Neuroscience 24: 478–480. Sourkes TL (2000): How dopamine was recognised as a neurotransmitter: A personal view. Parkinsonism and Related Disorders 6: 63–67. Sourkes TL (2002a): Magendie and the chemists: The earliest chemical analyses of the cerebrospinal fluid. Journal of the History of the Neurosciences 11: 2–10. Sourkes TL (2002b): William Mestrezat (1883–1928): Oenologist, physician, neurochemist. Journal of Medical Biography 10: 141–145. Sourkes TL (2003): The Life and Work of J. L. W. Thudichum 1829–1901 “. . . A Most Celebrated Exponent of the Art of Medicine and Chemistry,” Osler Library Studies in the History of Medicine, Number 9. Montréal, Osler Library, McGill University. Sourkes TL (2004): Social and medical origins of neurochemistry. Progress in NeuroPsychopharmacology and Biological Psychiatry 28: 885–890. Sourkes TL (2006a): On the energy cost of mental effort. Journal of the History of the Neurosciences 15: 31–47. Sourkes TL (2006b): Introduction: Neuroscience in the Nobel perspective. Journal of the History of the Neurosciences 15: 306–317. Sourkes TL (2007): Thudichum’s successors. Neurochemistry Research 32: 1808–1812. Sourkes TL (2009): Acetylcholine — From Vagusstoff to cerebral neurotransmitter. Journal of the History of the Neurosciences 18: 47–58. Sourkes TL (2010): The discovery of neurotransmitters, and applications to neurology. In: Finger S, Boller F, Tyler KL, ed., History of Neurology, Handbook of Clinical Neurology 95, third series. Edinburgh, Elsevier, pp. 869–883. Sourkes TL, Pinard G, eds. (1995): Building on a Proud Past. 50 Years of Psychiatry at McGill. Montréal, McGill University. Sourkes TL, Stevenson LG (1967): Nobel Prize Winners in Medicine and Physiology, 1901–1965. London, New York, Abelard-Schuman.

Cited publications by other authors Carlsson A (1959): The occurrence, distribution and physiological role of catecholamines in the nervous system. Pharmacological Reviews 11: 490–493. Carlsson A, Lindqvist M, Magnusson T (1957): 3,4-Dihydroxyphenylalanine and 5-hydroxytryptophan as reserpine antagonists. Nature 180: 1200. Ehringer H, Hornykiewicz O (1960): Verteilung von Noradrenalin und Dopamin (3Hydroxytyramin) im Gehirn des Menschen und ihr Verhalten bei Erkrankungen des extrapyramidalen Systems. Klinische Wochenschrift 38: 1236–1239.

Theodore L. Sourkes PhD, FRSC, OC (February 21, 1919-January 17, 2015).

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