Hartmann F. Stähelin
Encyclopedia
Hartmann F. Stähelin, M.D. (October 20, 1925 – July 5, 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
.
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 protoplast
s, called gymnoplasts, which had left behind their empty cell wall
s. 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.
Medical School). In 1955, Stähelin rediscovered the respiratory burst
in leucocyte
s 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).
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 October 21, 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, antimetabolite
s and Vinca alkaloids. After a landmark clinical comparative analysis by F. Muggia and M. Rozencweig, etoposide and teniposide were licenced 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 lymphoma
s and lung cancer
. It is also indispensable in the cure of testicular carcinoma
.
, brefeldin A
, verrucarin A, anguinine and chlamydocin, which have played an important role in basic cancer research.
In 1969, Stähelin made the key decision to include a test system for immunosuppression
into the general screening program at Sandoz for compounds and extracts. He invented a new procedure which permitted the use of the same mice for testing both anticancer activity (L-1210) and immunosuppression (inhibition of antibody formation) in an "all in one in-vivo test system". This considerably reduced both the number of experimental animals and the quantity of test substances required, and also decreased the labour involved. Stähelin's invention of this procedure initiated an innovative screening system for discovering immunosuppressant drugs lacking bone marrow toxicity – the first such screen to be discovered. This screening process was first used in the pharmacology department in January 1970, before Jean F. Borel joined Stähelin's group.
Stähelin had used a similar screen to discover the nonmyelotoxic immunosuppressant ovalicin. Applying the revised screen led to the discovery of the potent biological activity of ciclosporin
on January 31, 1972. This drug was to revolutionize organ transplantation in the 1970s and the paper became a citation classic (CC/6:16-16, February 6, 1984).
The "Stähelin Screen" was rapidly and very successfully adopted by the Japanese pharmaceutical company Fujisawa (now Astellas), which subsequently discovered tacrolimus
(FK-506, Prograf), the second clinically used calcineurin inhibitor.
On receiving the American Association for Cancer Research
Bruce F. Cain Award jointly with his colleague A. von Wartburg in 1990, Stähelin wrote:
"...there are an astonishing number of coincidences between etoposide and cyclosporine. The first coincidence was that etoposide and cyclosporine were both found and developed on the chemical and biological side by the same groups, those of the present authors and their specific biological effects were discovered by one of us; second, both compounds were approved by the United States Food and Drug Administration on the same day in November 1983, although they had been submitted by different companies; furthermore, both drugs act via an effect on an intranuclear isomerase, topoisomerase II, and peptide cis-trans-isomerase, respectively; both compounds are potent immunosuppressants; etoposide as well as cyclosporine are used in the treatment of leukemias or other malignancies; the latter after bone marrow transplantation to prevent graft-versus-host disease
, the former also being used in conjunction with bone marrow transplantation; sometimes, the two compounds are used concomitantly, exploiting the capacity of cyclosporine to reduce certain types of multidrug resistance or to modify immunity against tumors cured by etoposide; in the development of both drugs, galenical problems arose, related to poor water solubility and absorption from intestinal tract, and experience gained with etoposide in this area was crucial for overcoming, several years later, difficulties of a similar type with cyclosporine. It is left to the reader to make assumptions about the heuristic aspects of these surprising coincidences..."
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
and immunology
Immunology
Immunology is a broad branch of biomedical science that covers the study of all aspects of the immune system in all organisms. It deals with the physiological functioning of the immune system in states of both health and diseases; malfunctions of the immune system in immunological disorders ; the...
research. He discovered two important drugs: etoposide
Etoposide
Etoposide phosphate is an anti-cancer agent. It is known in the laboratory as a topoisomerase poison. Etoposide is often incorrectly referred to as a topoisomerase inhibitor in order to avoid using the term "poison" in a clinical setting...
and ciclosporin
Ciclosporin
Ciclosporin , cyclosporine , cyclosporin , or cyclosporin A is an immunosuppressant drug widely used in post-allogeneic organ transplant to reduce the activity of the immune system, and therefore the risk of organ rejection...
.
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, ZürichZürich
Zurich is the largest city in Switzerland and the capital of the canton of Zurich. It is located in central Switzerland at the northwestern tip of Lake Zurich...
and Florence
Florence
Florence is the capital city of the Italian region of Tuscany and of the province of Florence. It is the most populous city in Tuscany, with approximately 370,000 inhabitants, expanding to over 1.5 million in the metropolitan area....
(1944–1950). His first position after graduation was at the Institute of Microbiology of the University of Basel
University of Basel
The University of Basel is located in Basel, Switzerland, and is considered to be one of leading universities in the country...
(1951–1954) where he investigated the morphology and sporulation of anthrax
Anthrax
Anthrax is an acute disease caused by the bacterium Bacillus anthracis. Most forms of the disease are lethal, and it affects both humans and other animals...
bacilli with the help of the then-new phase contrast microscope. In May 1951, Stähelin was the first to observe naked anthrax bacilli protoplast
Protoplast
Protoplast, from the ancient Greek πρῶτον + verb πλάθω or πλάττω , initially referred to the first organized body of a species.Protoplast has several biological definitions:...
s, called gymnoplasts, which had left behind their empty cell wall
Cell wall
The cell wall is the tough, usually flexible but sometimes fairly rigid layer that surrounds some types of cells. It is located outside the cell membrane and provides these cells with structural support and protection, and also acts as a filtering mechanism. A major function of the cell wall is to...
s. A year later, during his studies of their osmotic
Osmosis
Osmosis is the movement of solvent molecules through a selectively permeable membrane into a region of higher solute concentration, aiming to equalize the solute concentrations on the two sides...
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
Joshua Lederberg
Joshua Lederberg ForMemRS was an American molecular biologist known for his work in microbial genetics, artificial intelligence, and the United States space program. He was just 33 years old when he won the 1958 Nobel Prize in Physiology or Medicine for discovering that bacteria can mate and...
, 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 FloridaUniversity of Florida
The University of Florida is an American public land-grant, sea-grant, and space-grant research university located on a campus in Gainesville, Florida. The university traces its historical origins to 1853, and has operated continuously on its present Gainesville campus since September 1906...
Medical School). In 1955, Stähelin rediscovered the respiratory burst
Respiratory burst
Respiratory burst is the rapid release of reactive oxygen species from different types of cells....
in leucocyte
Leucocyte
Leucocyte may refer to:*White blood cells*Leucocyte , a 2008 album by the jazz band E.S.T....
s in Manfred L. Karnovsky's laboratory at the Department of Bacteriology and Immunology, Harvard Medical School
Harvard Medical School
Harvard Medical School is the graduate medical school of Harvard University. It is located in the Longwood Medical Area of the Mission Hill neighborhood of Boston, Massachusetts....
, Boston
Boston
Boston is the capital of and largest city in Massachusetts, and is one of the oldest cities in the United States. The largest city in New England, Boston is regarded as the unofficial "Capital of New England" for its economic and cultural impact on the entire New England region. The city proper had...
, 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
Oxygen
Oxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...
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
Sandoz
Founded in 2003, Sandoz presently is the generic drug subsidiary of Novartis, a multinational pharmaceutical company. The company develops, manufactures and markets generic drugs as well as pharmaceutical and biotechnological active ingredients....
Corp. (now Novartis
Novartis
Novartis International AG is a multinational pharmaceutical company based in Basel, Switzerland, ranking number three in sales among the world-wide industry...
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 PodophyllumPodophyllum
Podophyllum is a genus of six species of herbaceous perennial plants in the family Berberidaceae, native to eastern Asia and eastern North America...
compounds; four of them, including etoposide
Etoposide
Etoposide phosphate is an anti-cancer agent. It is known in the laboratory as a topoisomerase poison. Etoposide is often incorrectly referred to as a topoisomerase inhibitor in order to avoid using the term "poison" in a clinical setting...
(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
Teniposide
Teniposide is a chemotherapeutic medication mainly used in the treatment of childhood acute lymphocytic leukemia . It is in a class of drugs known as podophyllotoxin derivatives and slows the growth of cancer cells in the body....
, Vumon, discovered in October 1965, commercialized by Sandoz in 1976) and to the ethylidene derivative VP-16-213 (etoposide, Vepesid, discovered on October 21, 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
Mitosis
Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly...
(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, antimetabolite
Antimetabolite
An antimetabolite is a chemical that inhibits the use of a metabolite, which is another chemical that is part of normal metabolism. Such substances are often similar in structure to the metabolite that they interfere with, such as the antifolates that interfere with the use of folic acid...
s and Vinca alkaloids. After a landmark clinical comparative analysis by F. Muggia and M. Rozencweig, etoposide and teniposide were licenced 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 lymphoma
Lymphoma
Lymphoma is a cancer in the lymphatic cells of the immune system. Typically, lymphomas present as a solid tumor of lymphoid cells. Treatment might involve chemotherapy and in some cases radiotherapy and/or bone marrow transplantation, and can be curable depending on the histology, type, and stage...
s and lung cancer
Lung cancer
Lung cancer is a disease characterized by uncontrolled cell growth in tissues of the lung. If left untreated, this growth can spread beyond the lung in a process called metastasis into nearby tissue and, eventually, into other parts of the body. Most cancers that start in lung, known as primary...
. It is also indispensable in the cure of testicular carcinoma
Testicular cancer
Testicular cancer is cancer that develops in the testicles, a part of the male reproductive system.In the United States, between 7,500 and 8,000 diagnoses of testicular cancer are made each year. In the UK, approximately 2,000 men are diagnosed each year. Over his lifetime, a man's risk of...
.
New screening process and the discovery of immunosuppressants
Stähelin was also instrumental in the discovery process of several microbial products inhibiting cell proliferation, including cytochalasin BCytochalasin B
Cytochalasin B is a cell-permeable mycotoxin. It inhibits cytoplasmic division by blocking the formation of contractile microfilaments. It inhibits cell movement and induces nuclear extrusion. Cytochalasin B shortens actin filaments by blocking monomer addition at the fast-growing end of polymers....
, brefeldin A
Brefeldin A
Brefeldin A is a lactone antibiotic produced by fungal organisms such as Eupenicillium brefeldianum. Brefeldin A inhibits transport of proteins from ER to Golgi and induces retrograde protein transport from the Golgi apparatus to the endoplasmic reticulum. This leads to proteins accumulating inside...
, verrucarin A, anguinine and chlamydocin, which have played an important role in basic cancer research.
In 1969, Stähelin made the key decision to include a test system for immunosuppression
Immunosuppression
Immunosuppression involves an act that reduces the activation or efficacy of the immune system. Some portions of the immune system itself have immuno-suppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse reaction to treatment of other...
into the general screening program at Sandoz for compounds and extracts. He invented a new procedure which permitted the use of the same mice for testing both anticancer activity (L-1210) and immunosuppression (inhibition of antibody formation) in an "all in one in-vivo test system". This considerably reduced both the number of experimental animals and the quantity of test substances required, and also decreased the labour involved. Stähelin's invention of this procedure initiated an innovative screening system for discovering immunosuppressant drugs lacking bone marrow toxicity – the first such screen to be discovered. This screening process was first used in the pharmacology department in January 1970, before Jean F. Borel joined Stähelin's group.
Stähelin had used a similar screen to discover the nonmyelotoxic immunosuppressant ovalicin. Applying the revised screen led to the discovery of the potent biological activity of ciclosporin
Ciclosporin
Ciclosporin , cyclosporine , cyclosporin , or cyclosporin A is an immunosuppressant drug widely used in post-allogeneic organ transplant to reduce the activity of the immune system, and therefore the risk of organ rejection...
on January 31, 1972. This drug was to revolutionize organ transplantation in the 1970s and the paper became a citation classic (CC/6:16-16, February 6, 1984).
The "Stähelin Screen" was rapidly and very successfully adopted by the Japanese pharmaceutical company Fujisawa (now Astellas), which subsequently discovered tacrolimus
Tacrolimus
Tacrolimus is an immunosuppressive drug that is mainly used after allogeneic organ transplant to reduce the activity of the patient's immune system and so lower the risk of organ rejection...
(FK-506, Prograf), the second clinically used calcineurin inhibitor.
On receiving the American Association for Cancer Research
American Association for Cancer Research
The American Association for Cancer Research is the world's oldest and largest professional association to advancing cancer research. Based in Philadelphia, AACR focuses on all aspects of cancer research including basic, clinical and translational research into the etiology, prevention, diagnosis,...
Bruce F. Cain Award jointly with his colleague A. von Wartburg in 1990, Stähelin wrote:
"...there are an astonishing number of coincidences between etoposide and cyclosporine. The first coincidence was that etoposide and cyclosporine were both found and developed on the chemical and biological side by the same groups, those of the present authors and their specific biological effects were discovered by one of us; second, both compounds were approved by the United States Food and Drug Administration on the same day in November 1983, although they had been submitted by different companies; furthermore, both drugs act via an effect on an intranuclear isomerase, topoisomerase II, and peptide cis-trans-isomerase, respectively; both compounds are potent immunosuppressants; etoposide as well as cyclosporine are used in the treatment of leukemias or other malignancies; the latter after bone marrow transplantation to prevent graft-versus-host disease
Graft-versus-host disease
Graft-versus-host disease is a common complication after a stem cell transplant or bone marrow transplant from another person . Immune cells in the donated marrow or stem cells recognize the recipient as "foreign". The transplanted immune cells then attack the host's body cells...
, the former also being used in conjunction with bone marrow transplantation; sometimes, the two compounds are used concomitantly, exploiting the capacity of cyclosporine to reduce certain types of multidrug resistance or to modify immunity against tumors cured by etoposide; in the development of both drugs, galenical problems arose, related to poor water solubility and absorption from intestinal tract, and experience gained with etoposide in this area was crucial for overcoming, several years later, difficulties of a similar type with cyclosporine. It is left to the reader to make assumptions about the heuristic aspects of these surprising coincidences..."