- Email: [email protected]
Kurt Stern (1909-2003)
PIONEERS AND PATHFINDERS Kurt Stern (1909-2003) S. Gerald Sandler, Noga Manny, and Eilat Shinar Solutions to problems in biology almost invariably lead to as many, and sometimes more, new questions that are left unanswered by the newly acquired information. The discovery that maternal isosensitization to the Rh factor is the most frequent cause of hemolytic disease of the newborn was no exception to this maxim. — Kurt Stern, 19561
N 1943, PHILIP LEVINE reported the unexplained and intriguing observation that women were more likely to form Rh antibodies (anti-D) if they lacked natural isoagglutinins (anti-A, -B) to their offspring’s red blood cells, when compared with women who had such isoagglutinins. By 1956, other scientists had confirmed Levine’s observation, but the mechanism(s) by which ABO isoagglutinins inhibited the formation of Rh antibodies was not known. Leading scientists proposed various hypotheses. Sir Robert Fisher suggested that ABO-incompatible offspring were aborted more frequently, decreasing the chance of maternal immunization. Alexander Wiener proposed that there was competition between A or B antigens and Rh antigens, resulting in unfavorable conditions for forming Rh antibodies. Robert Race and Ruth Sanger suggested that maternal ABO isoagglutinins caused rapid destruction of incompatible fetal red blood cells entering the maternal circulation, reducing their chance to stimulate maternal Rh antibodies.
I
From the Departments of Pathology and Medicine, Georgetown University Medical Center, Washington, DC; Department of Blood Bank, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; and Blood Services, Magen David Adom, Tel Hashomer, Israel. Address reprint requests to S. Gerald Sandler, MD, Department of Laboratory Medicine, Georgetown University Hospital, 3800 Reservoir Road, N.W., Washington, DC 20007. E-mail: [email protected] 0887-7963/05/$ – see front matter n 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.tmrv.2005.08.008
80
Kurt Stern, then Director of the Blood Center, Mount Sinai Medical Research Foundation, and Associate Professor of Pathology at the Chicago Medical School, applied to the National Institutes of Health for a grant to elucidate the scientific basis for Levine’s observation. His application was approved and the results of his research are now the foundation of our present understanding of Rh immunoprophylaxis. As an immunologist, Stern approached the problem of Rh hemolytic disease of the newborn by studying the interaction of ABO and Rh antigens in men and, thereby, separated the immunological from the maternal-fetal interactions. Together with Israel Davidsohn, Professor and Chairman of the Department of Pathology, and Lillian Masaitis, his research technician, Stern injected Rh-positive red cells into 39 male subjects. For 17 subjects, the Rh-positive red cells were ABO-compatible; for 22, the red cells were ABO-incompatible. Ten of the 17 subjects receiving ABO-compatible red cells formed Rh antibodies, but only 2 of the 22 receiving ABO-incompatible RBCs formed Rh antibodies. Stern published his findings in 1956, concluding that the effect of ABO on abortion (or conception) was excluded and that bat present, it seems to us that rapid elimination of antigen from the host is a highly probable explanation for the low incidence and low levels of Rh antibodies in Rh-negative persons who are injected with Rh-positive, ABOincompatible blood.Q1 Stern followed up with a second study designed to bfurnish some insight into the mechanism(s) of interference of ABO-incompatibility with Rh sensitization, and also some tentative generalizations concerning factors influencing immune responses to red cell isoantigens.Q2 He tested the hypothesis that rapid coating of ABO-incompatible Rh-positive red cells inhibited the of formation of Rh antibodies by Rh-negative subjects by injecting 8 group A, Rh-negative subjects with group A, Rh-positive red cells that had been coated in vitro with anti-A. Five group A Rh-negative
Transfusion Medicine Reviews, Vol 20, No 1 (January), 2006: pp 80-83
KURT STERN (1909 - 2003)
subjects (controls) were injected with non-coated Rh-positive red cells. Six of the 8 Rh-negative subjects who received coated red cells and all 5 subjects who received non-coated red cells developed Rh antibodies. Stern summarized these findings stating, bthere was no significant interference with Rh sensitization as a result of the dcoatingT in vitro with anti-A antibody of ABOcompatible Rh-positive blood.Q He then studied bthe effect of dcoatingT of Rh-positive cells in vitro with Rh antibodies on their ability to induce Rh sensitization.Q In what was to become a landmark study, he injected 16 group O, Rh-negative men with group O, R1 (CDe) red cells that had been coated in vitro with anti-Rho’ (anti-CD). None of the men developed Rh antibodies. Furthermore, of 10 men who did not develop Rh antibodies when injected with bcoatedQ red cells, 5 did develop Rh antibodies when subsequently injected with non-coated red cells. Stern summarized his two major findings as follows. First, binjection into Rh-negative men of Rh-positive blood coated in vitro with Rh antibodies was completely ineffective in inducing Rh antibodies.Q Second, bThe presence of large numbers of antibody-forming cells for one red cell factor may interfere with an antibody response to another blood factor contained in the same red cell.Q Stern achieved his goal of elucidating the immunological basis for Levine’s clinical observation. More importantly, he was the first scientist to demonstrate that Rh-positive red cells coated with Rh antibody did not stimulate the formation of Rh antibodies in Rh-negative recipients. Stern reported his results at the Annual Meeting of the American Association of Blood Banks in San Francisco in 1960 and published a full report in 1961.2 As a physician-immunologist, he focused on the immunological mechanism of blood group immunoprophylaxis, not on the practical application of these principles for Rh immunoprophylaxis in Rh-negative mothers. In 1972, Stern was honored by the American Association of Blood Banks as the John Elliot awardee for his original research on the immunological basis for ABO-Rh interactions, as well as for his other fundamental discoveries in blood bank immunology. David Zimmerman, who chronicled the history of Rh immunoprophylaxis in his book Rh, asked Stern how he felt about other scientists receiving worldwide recognition because they had applied
81
the immunological principles to the development of RhoGAM and had actually prevented Rh sensitization in Rh-negative mothers. Zimmerman described Stern’s response as follows: Asked how he could have come so close and yet missed the import of his own experiments, Stern laughed and replied, bThe human brain, including that of the research worker, does not always think things out in a logical way.Q Stern, a gentleman, has staked no retroactive claims. What had been his feelings on learning what others had made out of experiments very much like his own? bI had no misgivings at all, Q he says. bI wished them the best of luck!Q3
Subsequently, Zimmerman presented Stern with a personal copy of his book Rh, which he inscribed, bTo Kurt Stern—the straightest tree in the forest.Q Kurt Stern was born in Vienna, Austria, in 1909 and graduated from the University of Vienna School of Medicine in 1933 at age 23. As Jews were not eligible for salaried positions in Vienna of the 1930s, Stern held a non-salaried position at the Institute for Chemical Research. His first scientific journal article on cancer research was published in Wiener Klinische Wochenschrift. Shortly after, Stern and his mentor, Dr Robert Wilheim, coauthored the first comprehensive survey and critical evaluation of all biochemical cancer research to that date, Die Wege and Ergebnisse chemischer Krebsforschung (Vienna: Aeskulap-Verlag, 1936). After Stern’s immigration
Fig 1. Dr Kurt Stern, Blood Center, Mount Sinai Hospital, Chicago, Ill, 1957 (courtesy of Ms Shirley Busch).
82
SANDLER, MANNY AND SHINAR
Fig 2. Dr Philip Levine (left), Dr Kurt Stern (center), and Dr Cyril Levene (right), Jerusalem, Israel, 1974 (courtesy of Dr Cyril Levene).
to the United States, it was published in an English translation, The Biochemistry of Malignant Tumors (Brooklyn NY: Reference Press, 1943). In 1938, after Hitler’s bAnschlussQ in Austria, he immigrated to the United States and began a 21- year career, most of which was spent at the Mount Sinai Hospital and Chicago School of Medicine and at the University of Illinois Medical School and research facilities (Fig 1). During this phase of his career, his contributions focused on the immunological basis of blood banking, including descriptions of new blood group antigens, a new method for crossmatching with activated papain, and laboratory methods for improving transfusion safety. Together with Israel Davidson, he described the presence of anti-sheep agglutinins in infectious mononucleosis, which led to their developing the differential test for infectious mononucleosis in 1951. As an early pioneer in blood banking in the United States, Stern served on the Editorial Board of the American Journal of Clinical Pathology for 24 years, AABB’s Board of Directors, and as Scientific Director of the Bulletin of the American Association of Blood Banks. He was a member of Transfusion’s first Editorial Board. In 1969, Stern immigrated to Israel, fulfilling a lifelong dream. He served as the first Professor of Life Sciences at Bar Ilan University in Tel Aviv and, subsequently, as Research Professor at the Lautenberg Center for General and Tumor Immunology at the Hadassah-Hebrew University Medical Center in
Jerusalem (Figs 2 and 3). In Jerusalem, he returned to cancer research, his first career interest, but his reputation as a world-class blood bank immunohematologist followed him. In 1978, Stern was recruited to train the new Director of the Blood Bank at the Hebrew University Hadassah Hospital in Jerusalem and to assume additional administrative and advisory roles, but his primary interest and focus remained with cancer research. His publications on the role of the macrophage and the reticuloendothelial system in cancer appeared in the most prestigious journals, including Nature, Proceedings of the Society of Experimental Biology
Fig 3. Dr Kurt Stern, Jerusalem, Israel, 2002 (courtesy of Mrs Bracha Slae).
KURT STERN (1909 - 2003)
83
and Medicine, Clinical Experimental Immunology, and Journal of the National Cancer Institute. Kurt Stern died in Jerusalem in 2003 at the age of 94. He had published more than 150 scientific journal articles, 11 chapters in textbooks, and coauthored a textbook that had been published in both German and English. He worked in his laboratory at the Lautenberg Center well into his 90s. His last journal article, a study of macrophagetumor interactions, was published in In Vitro when he was 92 years old. Kurt Stern is remembered for his scientific contributions in the development
of Rh immunoprophylaxis and in cancer immunology, but perhaps most of all, for his integrity, vision for blood banking, and dedication to his many students and colleagues. ACKNOWLEDGMENTS
The authors thank the following persons who provided information on the life and contributions of Dr Stern: Bracha (Stern) Slae, Professor Josef Stern, Professor David Stern, Ms Shirley Busch, Dr John T. Queenan, and Dr Jack Nusbacher.
REFERENCES 1. Stern K, Davidshon I, Masaites L: Experimental studies on Rh immunization. Am J Clin Pathol 26:833 - 843, 1956 2. Stern K, Goodman H, Berger M: Experimental isoimmunization to hemoantigens in man. J Immun 87:189 - 198, 1961
3. Zimmerman DR: Rh/The intimate history of the disease and its conquest. New York, NY, Macmillan Publishing Co., Inc., 1973, pp 319 - 320
N 1943, PHILIP LEVINE reported the unexplained and intriguing observation that women were more likely to form Rh antibodies (anti-D) if they lacked natural isoagglutinins (anti-A, -B) to their offspring’s red blood cells, when compared with women who had such isoagglutinins. By 1956, other scientists had confirmed Levine’s observation, but the mechanism(s) by which ABO isoagglutinins inhibited the formation of Rh antibodies was not known. Leading scientists proposed various hypotheses. Sir Robert Fisher suggested that ABO-incompatible offspring were aborted more frequently, decreasing the chance of maternal immunization. Alexander Wiener proposed that there was competition between A or B antigens and Rh antigens, resulting in unfavorable conditions for forming Rh antibodies. Robert Race and Ruth Sanger suggested that maternal ABO isoagglutinins caused rapid destruction of incompatible fetal red blood cells entering the maternal circulation, reducing their chance to stimulate maternal Rh antibodies.
I
From the Departments of Pathology and Medicine, Georgetown University Medical Center, Washington, DC; Department of Blood Bank, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; and Blood Services, Magen David Adom, Tel Hashomer, Israel. Address reprint requests to S. Gerald Sandler, MD, Department of Laboratory Medicine, Georgetown University Hospital, 3800 Reservoir Road, N.W., Washington, DC 20007. E-mail: [email protected] 0887-7963/05/$ – see front matter n 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.tmrv.2005.08.008
80
Kurt Stern, then Director of the Blood Center, Mount Sinai Medical Research Foundation, and Associate Professor of Pathology at the Chicago Medical School, applied to the National Institutes of Health for a grant to elucidate the scientific basis for Levine’s observation. His application was approved and the results of his research are now the foundation of our present understanding of Rh immunoprophylaxis. As an immunologist, Stern approached the problem of Rh hemolytic disease of the newborn by studying the interaction of ABO and Rh antigens in men and, thereby, separated the immunological from the maternal-fetal interactions. Together with Israel Davidsohn, Professor and Chairman of the Department of Pathology, and Lillian Masaitis, his research technician, Stern injected Rh-positive red cells into 39 male subjects. For 17 subjects, the Rh-positive red cells were ABO-compatible; for 22, the red cells were ABO-incompatible. Ten of the 17 subjects receiving ABO-compatible red cells formed Rh antibodies, but only 2 of the 22 receiving ABO-incompatible RBCs formed Rh antibodies. Stern published his findings in 1956, concluding that the effect of ABO on abortion (or conception) was excluded and that bat present, it seems to us that rapid elimination of antigen from the host is a highly probable explanation for the low incidence and low levels of Rh antibodies in Rh-negative persons who are injected with Rh-positive, ABOincompatible blood.Q1 Stern followed up with a second study designed to bfurnish some insight into the mechanism(s) of interference of ABO-incompatibility with Rh sensitization, and also some tentative generalizations concerning factors influencing immune responses to red cell isoantigens.Q2 He tested the hypothesis that rapid coating of ABO-incompatible Rh-positive red cells inhibited the of formation of Rh antibodies by Rh-negative subjects by injecting 8 group A, Rh-negative subjects with group A, Rh-positive red cells that had been coated in vitro with anti-A. Five group A Rh-negative
Transfusion Medicine Reviews, Vol 20, No 1 (January), 2006: pp 80-83
KURT STERN (1909 - 2003)
subjects (controls) were injected with non-coated Rh-positive red cells. Six of the 8 Rh-negative subjects who received coated red cells and all 5 subjects who received non-coated red cells developed Rh antibodies. Stern summarized these findings stating, bthere was no significant interference with Rh sensitization as a result of the dcoatingT in vitro with anti-A antibody of ABOcompatible Rh-positive blood.Q He then studied bthe effect of dcoatingT of Rh-positive cells in vitro with Rh antibodies on their ability to induce Rh sensitization.Q In what was to become a landmark study, he injected 16 group O, Rh-negative men with group O, R1 (CDe) red cells that had been coated in vitro with anti-Rho’ (anti-CD). None of the men developed Rh antibodies. Furthermore, of 10 men who did not develop Rh antibodies when injected with bcoatedQ red cells, 5 did develop Rh antibodies when subsequently injected with non-coated red cells. Stern summarized his two major findings as follows. First, binjection into Rh-negative men of Rh-positive blood coated in vitro with Rh antibodies was completely ineffective in inducing Rh antibodies.Q Second, bThe presence of large numbers of antibody-forming cells for one red cell factor may interfere with an antibody response to another blood factor contained in the same red cell.Q Stern achieved his goal of elucidating the immunological basis for Levine’s clinical observation. More importantly, he was the first scientist to demonstrate that Rh-positive red cells coated with Rh antibody did not stimulate the formation of Rh antibodies in Rh-negative recipients. Stern reported his results at the Annual Meeting of the American Association of Blood Banks in San Francisco in 1960 and published a full report in 1961.2 As a physician-immunologist, he focused on the immunological mechanism of blood group immunoprophylaxis, not on the practical application of these principles for Rh immunoprophylaxis in Rh-negative mothers. In 1972, Stern was honored by the American Association of Blood Banks as the John Elliot awardee for his original research on the immunological basis for ABO-Rh interactions, as well as for his other fundamental discoveries in blood bank immunology. David Zimmerman, who chronicled the history of Rh immunoprophylaxis in his book Rh, asked Stern how he felt about other scientists receiving worldwide recognition because they had applied
81
the immunological principles to the development of RhoGAM and had actually prevented Rh sensitization in Rh-negative mothers. Zimmerman described Stern’s response as follows: Asked how he could have come so close and yet missed the import of his own experiments, Stern laughed and replied, bThe human brain, including that of the research worker, does not always think things out in a logical way.Q Stern, a gentleman, has staked no retroactive claims. What had been his feelings on learning what others had made out of experiments very much like his own? bI had no misgivings at all, Q he says. bI wished them the best of luck!Q3
Subsequently, Zimmerman presented Stern with a personal copy of his book Rh, which he inscribed, bTo Kurt Stern—the straightest tree in the forest.Q Kurt Stern was born in Vienna, Austria, in 1909 and graduated from the University of Vienna School of Medicine in 1933 at age 23. As Jews were not eligible for salaried positions in Vienna of the 1930s, Stern held a non-salaried position at the Institute for Chemical Research. His first scientific journal article on cancer research was published in Wiener Klinische Wochenschrift. Shortly after, Stern and his mentor, Dr Robert Wilheim, coauthored the first comprehensive survey and critical evaluation of all biochemical cancer research to that date, Die Wege and Ergebnisse chemischer Krebsforschung (Vienna: Aeskulap-Verlag, 1936). After Stern’s immigration
Fig 1. Dr Kurt Stern, Blood Center, Mount Sinai Hospital, Chicago, Ill, 1957 (courtesy of Ms Shirley Busch).
82
SANDLER, MANNY AND SHINAR
Fig 2. Dr Philip Levine (left), Dr Kurt Stern (center), and Dr Cyril Levene (right), Jerusalem, Israel, 1974 (courtesy of Dr Cyril Levene).
to the United States, it was published in an English translation, The Biochemistry of Malignant Tumors (Brooklyn NY: Reference Press, 1943). In 1938, after Hitler’s bAnschlussQ in Austria, he immigrated to the United States and began a 21- year career, most of which was spent at the Mount Sinai Hospital and Chicago School of Medicine and at the University of Illinois Medical School and research facilities (Fig 1). During this phase of his career, his contributions focused on the immunological basis of blood banking, including descriptions of new blood group antigens, a new method for crossmatching with activated papain, and laboratory methods for improving transfusion safety. Together with Israel Davidson, he described the presence of anti-sheep agglutinins in infectious mononucleosis, which led to their developing the differential test for infectious mononucleosis in 1951. As an early pioneer in blood banking in the United States, Stern served on the Editorial Board of the American Journal of Clinical Pathology for 24 years, AABB’s Board of Directors, and as Scientific Director of the Bulletin of the American Association of Blood Banks. He was a member of Transfusion’s first Editorial Board. In 1969, Stern immigrated to Israel, fulfilling a lifelong dream. He served as the first Professor of Life Sciences at Bar Ilan University in Tel Aviv and, subsequently, as Research Professor at the Lautenberg Center for General and Tumor Immunology at the Hadassah-Hebrew University Medical Center in
Jerusalem (Figs 2 and 3). In Jerusalem, he returned to cancer research, his first career interest, but his reputation as a world-class blood bank immunohematologist followed him. In 1978, Stern was recruited to train the new Director of the Blood Bank at the Hebrew University Hadassah Hospital in Jerusalem and to assume additional administrative and advisory roles, but his primary interest and focus remained with cancer research. His publications on the role of the macrophage and the reticuloendothelial system in cancer appeared in the most prestigious journals, including Nature, Proceedings of the Society of Experimental Biology
Fig 3. Dr Kurt Stern, Jerusalem, Israel, 2002 (courtesy of Mrs Bracha Slae).
KURT STERN (1909 - 2003)
83
and Medicine, Clinical Experimental Immunology, and Journal of the National Cancer Institute. Kurt Stern died in Jerusalem in 2003 at the age of 94. He had published more than 150 scientific journal articles, 11 chapters in textbooks, and coauthored a textbook that had been published in both German and English. He worked in his laboratory at the Lautenberg Center well into his 90s. His last journal article, a study of macrophagetumor interactions, was published in In Vitro when he was 92 years old. Kurt Stern is remembered for his scientific contributions in the development
of Rh immunoprophylaxis and in cancer immunology, but perhaps most of all, for his integrity, vision for blood banking, and dedication to his many students and colleagues. ACKNOWLEDGMENTS
The authors thank the following persons who provided information on the life and contributions of Dr Stern: Bracha (Stern) Slae, Professor Josef Stern, Professor David Stern, Ms Shirley Busch, Dr John T. Queenan, and Dr Jack Nusbacher.
REFERENCES 1. Stern K, Davidshon I, Masaites L: Experimental studies on Rh immunization. Am J Clin Pathol 26:833 - 843, 1956 2. Stern K, Goodman H, Berger M: Experimental isoimmunization to hemoantigens in man. J Immun 87:189 - 198, 1961
3. Zimmerman DR: Rh/The intimate history of the disease and its conquest. New York, NY, Macmillan Publishing Co., Inc., 1973, pp 319 - 320