Hartmann F. Stähelin (20 October 1925 – 5 July 2011) was a Swiss pharmacologist with an outstanding record in basic and applied cancer and immunology research. He discovered two important drugs: etoposide and ciclosporin.
Early life Both Stähelin's parents were medical doctors. After preparatory school and a classical education with the emphasis on Greek and Latin, Stähelin studied medicine in Basel, Zürich and Florence (1944–1950). His first position after graduation was at the Institute of Microbiology of the University of Basel (1951–1954) where he investigated the morphology and sporulation of anthrax bacilli with the help of the then-new phase-contrast microscope. In May 1951, Stähelin was the first to observe naked anthrax bacilli protoplasts, called gymnoplasts, which had left behind their empty cell walls. A year later, during his studies of their osmotic behavior, he discovered and described the occasional fusion of naked protoplasts. This seminal paper in German immediately caught the attention of the bacterial geneticist Joshua Lederberg, who personally requested a copy.
Early career In 1954, Stähelin successfully applied for a 12-month postdoctoral fellowship sponsored by the Swiss National Foundation (SNF) to work on a project on phagocytosis inspired by Emanuel Suter (then at Harvard, later second Dean of the University of Florida Medical School). In 1955, Stähelin rediscovered the respiratory burst in leucocytes in Manfred L. Karnovsky's laboratory at the Department of Bacteriology and Immunology, Harvard Medical School, Boston, U.S.A. His experiments stirred the interest of Karnovsky, who was at the time unaware of this metabolic phenomenon (which had first been described more than twenty years earlier in 1933 by C. W. Baldridge and R. W. Gerard). Stähelin's elegant work subsequently paved the way for the famous investigations of A.J. Sbarra and Karnovsky on the role of oxygen in the defense against microorganisms. While at Boston, the biomedical talent of the 27-year-old Stähelin was spotted by the director of the pharmacology department of the Sandoz Corp. (now Novartis AG.) Basel, who visited Suter's Harvard Medical School laboratory. After 6 months of training in the state-of-the art tissue-culture techniques in John F. Enders' laboratory in Boston, sponsored by Sandoz, Stähelin joined its pharmacology department in Basel to head the newly created laboratory, then a research group working on cancer and immunology (1955–1979).
Discovery of Podophyllum derivatives Stähelin quickly assumed the leading role in the discovery and development of Podophyllum compounds; four of them, including etoposide (Vepesid), were later marketed. He was able to detect in a partially purified, chemically modified extract of the Podophyllum plant the presence of a then-unknown agent with interesting properties, which had at first been considered by the chemists to be "dirt". The chemists, under the direction of A. von Wartburg, analysed this impurity. Guided by Stähelin's in-vitro and in-vivo assays, they found the active compound responsible for the good antitumor activity of SP-G (Proresid oral) and SP-I (Proresid intravenous; discovered in April 1959, commercialized 1963). Further chemical modifications led to the well-known thenylidene derivative VM-26 (teniposide, Vumon, discovered in October 1965, commercialized by Sandoz in 1976) and to the ethylidene derivative VP-16-213 (etoposide, Vepesid, discovered on 21 October 1966), which remains very clinically successful. Teniposide and etoposide were found by Stähelin to have a new mechanism of action: they blocked the entry of cells into mitosis (with arrest in late S or G2 phase), in contrast to SP-G and SP-I, which were spindle poisons. His subsequent investigations showed that the early biochemical effect of the two epipodophyllotoxins on proliferating cells in vitro differed from that of the alkylating agents, antimetabolites and Vinca alkaloids. After a landmark clinical comparative analysis by F. Muggia and M. Rozencweig, etoposide and teniposide were licensed to Bristol-Myers in 1978 for further clinical development. A few years later, in November 1983, etoposide was approved by the U.S. Food and Drug Administration. Etoposide is still considered a potent, well-tolerated combination partner in innumerable hematologic and solid tumor treatment schedules, including those for malignant lymphomas and lung cancer. It is also indispensable in the cure of testicular carcinoma.
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