0013-7227/91/1295-2274$03.00/0 Endocrinology Copyright © 1991 by The Endocrine Society
Vol. 129, No. 5 Printed in U.S.A.
Remembrance of Dr. Alfred Jost Dr. Alfred Jost died suddenly at his home, in the early morning of February 3, 1991, of a heart attack, at the age of 74. Just retired from the College of France, a prestigious school for higher education, he was still active in research, in spite of the demands made on his time by his duties as secretary of the French Academy of Science. Dr. Jost is rightly regarded as the father of modern fetal endocrinology. Up to 1950, birds were the favorite embryological models, because of the technical accessibility of the avian egg. Jost was the first to apply surgical techniques to the intrauterine mammalian fetus. By castrating fetal rabbits at an early, ambivalent stage, he succeeded in preventing male differentiation: the genetic males were born with persistent Miillerian ducts and no Wolffian derivatives (1). Were both effects due to the same cause? By comparing the effect on female fetal sex differentiation of an implanted testosterone crystal and a grafted testicular fragment, Alfred Jost proved the duality of fetal testicular secretin (Fig. 1) (2). In contrast to testicular tissue, testosterone was unable to induce the regression of the female sex primordia, and Jost logically concluded that another testicular hormone must be present to accomplish this task. He named this putative factor "1 'hormone inhibitrice," in English the "Miillerian inhibitor." Paradoxically, this hypothesis was better received by physicians abroad than by his fellow scientists. Etienne Wolff and his school continued for many years to uphold the theory that testosterone alone was responsible for Miillerian regression (3)... Through his brother, Dr. Marc Jost, who lived in Mexico City and was familiar with his experiments, Alfred Jost was invited to present his results at the First International Congress of Obstetrics and Gynecology, held in 1949 in Mexico City. On his return trip, he visited the Carnegie Institute in Washington, and one of the Embryology Associates, Dr. Robert K. Burns, suggested that he meet a clinician at Johns Hopkins, who was interested in human genital anomalies. One of Dr. Jost's favorite stories (4) was that of his first encounter with Dr. Lawson Wilkins. During a whole afternoon, the founder of pediatric endocrinology confronted the young Received May 29,1991. "Remembrance," articles discuss people and events as remembered by the author. The opinion(s) expressed are solely those of the writer and do not reflect the view of the Journal or The Endocrine Society.
Frenchman with cases of abnormal sex differentiation, Turner's syndrome, congenital adrenal hyperplasia, testicular feminization, and asked how the theory of the duality of fetal testicular secretion could explain the clinical picture. At the end of the day, Wilkins said: "I'm convinced!" He then undertook to "market" the Jost theory among American endocrinologists. The Nobel prize winners Gregory Pincus and Bernardo Houssay, followed by Howard W. Jones Jr., Melvin Grumbach, Maria New, Claude Migeon, to name only a few, became his fervent admirers and warm personal friends. An intellectual giant, Dr. Jost did not neglect the technical aspect of laboratory investigation. "Everyone can have ideas," he liked to say, "not everyone can carry them out." It took him a year and a half of hard work to successfully carry out the castration of fetal rabbits, (Fig. 2) and his technical difficulties were not alleviated by the fact that in hungry postwar Paris, rabbits were easier to obtain for the kitchen than for the laboratory. Having demonstrated the role of the fetal testis in sex differentiation, Jost developed another original technique to study its pituitary regulation. Knowing that some acephalic human fetuses had been described, he decided to try decapitating rabbit fetuses. The first three died, but the fourth survived several days, judging from its size. Later, encephalectomy was devised to remove the hypothalamus, while leaving the pituitary in situ. Fetal decapitation and encephalectomy became routine techniques in Jost's laboratory and were applied to the study of pituitary regulation of various organs: the testis (5), the thyroid (6), the adrenals (7), and the liver (8). However, sex differentiation always remained Jost's favorite subject. He devoted significant efforts to the study of freemartininism, and was the first to suggest that the ovarian aplasia and masculinization observed in female fetuses joined to male twins by placental anastomoses could be due to the factor responsible for Miillerian regression (9). Efforts to isolate the Miillerian inhibitor were initiated in his laboratory by Regine Picon: she showed that the fetal rat Miillerian duct, explanted in the absence of gonads at day-14 postcoitum, was a reliable and convenient target organ for testing anti-Miillerian activity (10). The Miillerian inhibitor, now called anti-Miillerian hormone, Miillerian-inhibiting substance or factor, was characterized as a glycoprotein dimer (11), purified from calf fetal testes (12) and culture medium
2274
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REMEMBRANCE
2275
WM
FIG. 1. Graphic reconstruction (slightly schematized) of genital tract of two female rabbit fetuses 28 days old. Top, Fetal testis (t) was grafted near ovary (ov) on day 20. Partial inhibition of Miillerian duct (M) and partial maintenance of Wolffian duct (W, stippled) resulted. Bottom, Crystal of testosterone propionate (cr) was implanted near ovary on day 20. There was maintenance of Wolffian ducts and no inhibition of the Miillerian ducts (from 20, with permission).
of transfected cells in culture (13), cloned (14), and localized on the human genome (15). A member of the TGF-/3 family (14,16), the hormone is now detectable by enzyme-linked immunosorbent assay in human serum (17) and a transgenic mouse line expressing human Miillerian inhibitor under the control of a heterologous promoter has been constructed (18). Jost's interest in his "baby's" progress never wavered, and is reflected in his last manuscript, published after his death (19). Dr. Jost's many admirers will be stunned to learn that this great scientist was initially destined to become a grocer's assistant. Young Alfred's father died when he was 13, and a year later, his mother became unable to care for her four sons. The two older boys were supporting themselves, the youngest was farmed out to his grandmother and Madame Jost was making arrangements with a grocer to employ Alfred, when Madame Oguse, a neighbor in the same building, touched by the boy's predicament, offered to raise him with her own children. Andre Oguse, a professor of ancient Greek at
FIG. 2. Castration of fetal rabbit at day-23 postco'itum. An uterine chamber has been opened, the posterior end of the fetus is exteriorized, its flank incised and the testis and mesonephros are exposed. After testicular resection, the fetus is replaced into the uterus. For practical reasons, the operation has been photographed using a fetus past the ambisexual stage, castration at that age would not be expected to result in female sex differentiation. From Ref. 19, with permission.
the University of Strasbourg, struck with the child's keen intelligence, tutored him so that the same year he rose from the bottom to the top of his class and, in 1936, was admitted to the prestigious Ecole Normale Superieure. Alfred's intellectual preoccupations did not however blind him to his surroundings: he fell head over heels in love with the young daughter of the house. When they were married in 1940, Christiane was 16. Their union lasted more than 50 years. Dr. Jost's pioneering contribution to developmental endocrinology ensures him an everlasting place in the scientific Pantheon. He will remain alive in the heart of those who had the privilege of knowing this great man. It is difficult, particularly for someone for whom English
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 10 May 2015. at 19:58 For personal use only. No other uses without permission. . All rights reserved.
REMEMBRANCE
2276
FIG. 3. Professor Alfred Jost
is not a native language, to find the words to describe his simplicity, his genuine interest in young people, his intellectual honesty, and the charm and authority which radiated from his person. In this picture taken at a meeting (Fig. 3), he seems about to speak. How hard it is for those who loved him to believe they will never hear his voice again... Unite de Recherches sur l'Endocrinologie du Developpement INSERM Ecole Normale Superieure Montrouge, France
References 1. Jost A1947 Recherches sur la differentiation sexuelle de l'embryon de lapin. III. Role des gonades foetales dans la differentiation
Endo • 1991 Voll29«No5
sexuelle somatique. Arch Anat Microsc Morphol Exp 36:271-315 2. Jost A 1953 Problems of fetal endocrinology: the gonadal and hypophyseal hormones. Rec Progr Horm Res 8:379-418 3. Lutz-Ostertag Y 1976 Nouvelles preuves de l'action de la testosterone sur le developpement des canaux de Miiller de l'embryon d'Oiseau en culture in vitro. CR Acad Sci Serie D Paris 278:23512353 4. Jost A 1972 A new look at the mechanisms controlling sex differentiation in mammals. Johns Hopkins Med J 130:38-53 5. Jost A 1951 Recherches sur la differentiation sexuelle de l'embryon de Lapin IV. Organogenese sexuelle masculine apres decapitation du foetus. Arch Anat Microsc Morphol Exp 40:247-281 6. Jost A 1953 Sur le developpement de la thyroide chez le foetus de Lapin decapite. Arch Anat Microsc Morphol Exp 42:168-183 7. Jost A, Cohen A 1966 Signification de l'"atrophie" des surrenales foetales du Rat provoquee par l'hypophysectomie (decapitation). Dev Biol 14:154-168 8. Jost A, Jacquot R 1954 Recherches sur le controle hormonal de la charge en glycogene du foie foetal du Lapin et du Rat. CR Acad Sci serie D Paris 239:98-100 9. Jost A, Vigier B, Prepin J 1972 Freemartins in cattle: the first steps of sexual organogenesis. J Reprod Fertil 29:349-379 10. Picon R 1969 Action du testicule foetal sur le developpement in vitro des canaux de Miiller chez le rat. Arch Anat Microsc Morphol Exp 58:1-19 11. Picard JY, Tran D, Josso N 1978 Biosynthesis of labeled antiMullerian hormone by fetal testes: evidence for the glycoprotein nature of the hormone and for its disulfide-bonded structure. Mol Cell Endocrinol 12:17-30 12. Picard JY, Josso N 1984 Purification of testicular anti-Mullerian hormone allowing direct visualization of the pure glycoprotein and determination of yield and purification factor. Mol Cell Endocrinol 34:23-29 13. Wallen J, Cate RL, Kiefer DM, Riemen MW, Martinez D, Hoffman RM, Donahoe PK, Von Hoff DD, Pepinsky B, Oliff A1989 Minimal anti-proliferative effect of recombinant Mullerian inhibiting substance on gynecological tumor cell lines and tumor explants. Cancer Res 49:2005-2011 14. Cate RL, Mattaliano RJ, Hession C, Tizard R, Farber NM, Cheung A, Ninfa EG, Frey AZ, Gash DJ, Chow EP, Fisher RA, Bertonis JM, Torres G, Wallner BP, Ramachandran KL, Ragin RC, Manganaro TF, MacLaughlin DT, Donahoe PK 1986 Isolation of the bovine and human genes for mullerian inhibiting substance and expression of the human gene in animal cells. Cell 45:685-698 15. Cohen-Haguenauer O, Picard JY, Mattei MG, Serero S, Nguyen VC, de Tand MF, Guerrier D, Hors-Cayla MC, Josso N, Frezal J 1987 Mapping of the gene for anti-Mullerian hormone to the short arm of human chromosome 19. Cytogenet Cell Genet 44:2-6 16. Pepinsky RB, Sinclair LK, Chow EP, Mattaliano RJ, Manganaro TF, Donahoe PK, Cate RL 1988 Proteolytic processing of Mullerian inhibiting substance produces a transforming growth factor-/? like fragment. J Biol Chem 263:18961-18965 17. Miller WL 1990 Immunoassays for human mullerian inhibitory factor (MIF)—new insights into the physiology of MIF. J Clin Endocrinol Metab 70:8-10 18. Behringer RR, Cate RL, Froelick GJ, Palmiter RD, Brinster RL 1990 Abnormal sexual development in transgenic mice chronically expressing Mullerian inhibiting substance. Nature 345:167-170 19. Jost A 1991 Les peripeties d'une recherche: l'etude de la differentiation sexuelle. Med Sci 7:264-275 20. Jost A 1955 La biologie des androgenes chez l'embryon. In: Hie Reunion des Endocrinologistes de Langue Francaise. Paris: Masson, pp 160-180
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 10 May 2015. at 19:58 For personal use only. No other uses without permission. . All rights reserved.
Vol. 129, No. 5 Printed in U.S.A.
Remembrance of Dr. Alfred Jost Dr. Alfred Jost died suddenly at his home, in the early morning of February 3, 1991, of a heart attack, at the age of 74. Just retired from the College of France, a prestigious school for higher education, he was still active in research, in spite of the demands made on his time by his duties as secretary of the French Academy of Science. Dr. Jost is rightly regarded as the father of modern fetal endocrinology. Up to 1950, birds were the favorite embryological models, because of the technical accessibility of the avian egg. Jost was the first to apply surgical techniques to the intrauterine mammalian fetus. By castrating fetal rabbits at an early, ambivalent stage, he succeeded in preventing male differentiation: the genetic males were born with persistent Miillerian ducts and no Wolffian derivatives (1). Were both effects due to the same cause? By comparing the effect on female fetal sex differentiation of an implanted testosterone crystal and a grafted testicular fragment, Alfred Jost proved the duality of fetal testicular secretin (Fig. 1) (2). In contrast to testicular tissue, testosterone was unable to induce the regression of the female sex primordia, and Jost logically concluded that another testicular hormone must be present to accomplish this task. He named this putative factor "1 'hormone inhibitrice," in English the "Miillerian inhibitor." Paradoxically, this hypothesis was better received by physicians abroad than by his fellow scientists. Etienne Wolff and his school continued for many years to uphold the theory that testosterone alone was responsible for Miillerian regression (3)... Through his brother, Dr. Marc Jost, who lived in Mexico City and was familiar with his experiments, Alfred Jost was invited to present his results at the First International Congress of Obstetrics and Gynecology, held in 1949 in Mexico City. On his return trip, he visited the Carnegie Institute in Washington, and one of the Embryology Associates, Dr. Robert K. Burns, suggested that he meet a clinician at Johns Hopkins, who was interested in human genital anomalies. One of Dr. Jost's favorite stories (4) was that of his first encounter with Dr. Lawson Wilkins. During a whole afternoon, the founder of pediatric endocrinology confronted the young Received May 29,1991. "Remembrance," articles discuss people and events as remembered by the author. The opinion(s) expressed are solely those of the writer and do not reflect the view of the Journal or The Endocrine Society.
Frenchman with cases of abnormal sex differentiation, Turner's syndrome, congenital adrenal hyperplasia, testicular feminization, and asked how the theory of the duality of fetal testicular secretion could explain the clinical picture. At the end of the day, Wilkins said: "I'm convinced!" He then undertook to "market" the Jost theory among American endocrinologists. The Nobel prize winners Gregory Pincus and Bernardo Houssay, followed by Howard W. Jones Jr., Melvin Grumbach, Maria New, Claude Migeon, to name only a few, became his fervent admirers and warm personal friends. An intellectual giant, Dr. Jost did not neglect the technical aspect of laboratory investigation. "Everyone can have ideas," he liked to say, "not everyone can carry them out." It took him a year and a half of hard work to successfully carry out the castration of fetal rabbits, (Fig. 2) and his technical difficulties were not alleviated by the fact that in hungry postwar Paris, rabbits were easier to obtain for the kitchen than for the laboratory. Having demonstrated the role of the fetal testis in sex differentiation, Jost developed another original technique to study its pituitary regulation. Knowing that some acephalic human fetuses had been described, he decided to try decapitating rabbit fetuses. The first three died, but the fourth survived several days, judging from its size. Later, encephalectomy was devised to remove the hypothalamus, while leaving the pituitary in situ. Fetal decapitation and encephalectomy became routine techniques in Jost's laboratory and were applied to the study of pituitary regulation of various organs: the testis (5), the thyroid (6), the adrenals (7), and the liver (8). However, sex differentiation always remained Jost's favorite subject. He devoted significant efforts to the study of freemartininism, and was the first to suggest that the ovarian aplasia and masculinization observed in female fetuses joined to male twins by placental anastomoses could be due to the factor responsible for Miillerian regression (9). Efforts to isolate the Miillerian inhibitor were initiated in his laboratory by Regine Picon: she showed that the fetal rat Miillerian duct, explanted in the absence of gonads at day-14 postcoitum, was a reliable and convenient target organ for testing anti-Miillerian activity (10). The Miillerian inhibitor, now called anti-Miillerian hormone, Miillerian-inhibiting substance or factor, was characterized as a glycoprotein dimer (11), purified from calf fetal testes (12) and culture medium
2274
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 10 May 2015. at 19:58 For personal use only. No other uses without permission. . All rights reserved.
REMEMBRANCE
2275
WM
FIG. 1. Graphic reconstruction (slightly schematized) of genital tract of two female rabbit fetuses 28 days old. Top, Fetal testis (t) was grafted near ovary (ov) on day 20. Partial inhibition of Miillerian duct (M) and partial maintenance of Wolffian duct (W, stippled) resulted. Bottom, Crystal of testosterone propionate (cr) was implanted near ovary on day 20. There was maintenance of Wolffian ducts and no inhibition of the Miillerian ducts (from 20, with permission).
of transfected cells in culture (13), cloned (14), and localized on the human genome (15). A member of the TGF-/3 family (14,16), the hormone is now detectable by enzyme-linked immunosorbent assay in human serum (17) and a transgenic mouse line expressing human Miillerian inhibitor under the control of a heterologous promoter has been constructed (18). Jost's interest in his "baby's" progress never wavered, and is reflected in his last manuscript, published after his death (19). Dr. Jost's many admirers will be stunned to learn that this great scientist was initially destined to become a grocer's assistant. Young Alfred's father died when he was 13, and a year later, his mother became unable to care for her four sons. The two older boys were supporting themselves, the youngest was farmed out to his grandmother and Madame Jost was making arrangements with a grocer to employ Alfred, when Madame Oguse, a neighbor in the same building, touched by the boy's predicament, offered to raise him with her own children. Andre Oguse, a professor of ancient Greek at
FIG. 2. Castration of fetal rabbit at day-23 postco'itum. An uterine chamber has been opened, the posterior end of the fetus is exteriorized, its flank incised and the testis and mesonephros are exposed. After testicular resection, the fetus is replaced into the uterus. For practical reasons, the operation has been photographed using a fetus past the ambisexual stage, castration at that age would not be expected to result in female sex differentiation. From Ref. 19, with permission.
the University of Strasbourg, struck with the child's keen intelligence, tutored him so that the same year he rose from the bottom to the top of his class and, in 1936, was admitted to the prestigious Ecole Normale Superieure. Alfred's intellectual preoccupations did not however blind him to his surroundings: he fell head over heels in love with the young daughter of the house. When they were married in 1940, Christiane was 16. Their union lasted more than 50 years. Dr. Jost's pioneering contribution to developmental endocrinology ensures him an everlasting place in the scientific Pantheon. He will remain alive in the heart of those who had the privilege of knowing this great man. It is difficult, particularly for someone for whom English
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 10 May 2015. at 19:58 For personal use only. No other uses without permission. . All rights reserved.
REMEMBRANCE
2276
FIG. 3. Professor Alfred Jost
is not a native language, to find the words to describe his simplicity, his genuine interest in young people, his intellectual honesty, and the charm and authority which radiated from his person. In this picture taken at a meeting (Fig. 3), he seems about to speak. How hard it is for those who loved him to believe they will never hear his voice again... Unite de Recherches sur l'Endocrinologie du Developpement INSERM Ecole Normale Superieure Montrouge, France
References 1. Jost A1947 Recherches sur la differentiation sexuelle de l'embryon de lapin. III. Role des gonades foetales dans la differentiation
Endo • 1991 Voll29«No5
sexuelle somatique. Arch Anat Microsc Morphol Exp 36:271-315 2. Jost A 1953 Problems of fetal endocrinology: the gonadal and hypophyseal hormones. Rec Progr Horm Res 8:379-418 3. Lutz-Ostertag Y 1976 Nouvelles preuves de l'action de la testosterone sur le developpement des canaux de Miiller de l'embryon d'Oiseau en culture in vitro. CR Acad Sci Serie D Paris 278:23512353 4. Jost A 1972 A new look at the mechanisms controlling sex differentiation in mammals. Johns Hopkins Med J 130:38-53 5. Jost A 1951 Recherches sur la differentiation sexuelle de l'embryon de Lapin IV. Organogenese sexuelle masculine apres decapitation du foetus. Arch Anat Microsc Morphol Exp 40:247-281 6. Jost A 1953 Sur le developpement de la thyroide chez le foetus de Lapin decapite. Arch Anat Microsc Morphol Exp 42:168-183 7. Jost A, Cohen A 1966 Signification de l'"atrophie" des surrenales foetales du Rat provoquee par l'hypophysectomie (decapitation). Dev Biol 14:154-168 8. Jost A, Jacquot R 1954 Recherches sur le controle hormonal de la charge en glycogene du foie foetal du Lapin et du Rat. CR Acad Sci serie D Paris 239:98-100 9. Jost A, Vigier B, Prepin J 1972 Freemartins in cattle: the first steps of sexual organogenesis. J Reprod Fertil 29:349-379 10. Picon R 1969 Action du testicule foetal sur le developpement in vitro des canaux de Miiller chez le rat. Arch Anat Microsc Morphol Exp 58:1-19 11. Picard JY, Tran D, Josso N 1978 Biosynthesis of labeled antiMullerian hormone by fetal testes: evidence for the glycoprotein nature of the hormone and for its disulfide-bonded structure. Mol Cell Endocrinol 12:17-30 12. Picard JY, Josso N 1984 Purification of testicular anti-Mullerian hormone allowing direct visualization of the pure glycoprotein and determination of yield and purification factor. Mol Cell Endocrinol 34:23-29 13. Wallen J, Cate RL, Kiefer DM, Riemen MW, Martinez D, Hoffman RM, Donahoe PK, Von Hoff DD, Pepinsky B, Oliff A1989 Minimal anti-proliferative effect of recombinant Mullerian inhibiting substance on gynecological tumor cell lines and tumor explants. Cancer Res 49:2005-2011 14. Cate RL, Mattaliano RJ, Hession C, Tizard R, Farber NM, Cheung A, Ninfa EG, Frey AZ, Gash DJ, Chow EP, Fisher RA, Bertonis JM, Torres G, Wallner BP, Ramachandran KL, Ragin RC, Manganaro TF, MacLaughlin DT, Donahoe PK 1986 Isolation of the bovine and human genes for mullerian inhibiting substance and expression of the human gene in animal cells. Cell 45:685-698 15. Cohen-Haguenauer O, Picard JY, Mattei MG, Serero S, Nguyen VC, de Tand MF, Guerrier D, Hors-Cayla MC, Josso N, Frezal J 1987 Mapping of the gene for anti-Mullerian hormone to the short arm of human chromosome 19. Cytogenet Cell Genet 44:2-6 16. Pepinsky RB, Sinclair LK, Chow EP, Mattaliano RJ, Manganaro TF, Donahoe PK, Cate RL 1988 Proteolytic processing of Mullerian inhibiting substance produces a transforming growth factor-/? like fragment. J Biol Chem 263:18961-18965 17. Miller WL 1990 Immunoassays for human mullerian inhibitory factor (MIF)—new insights into the physiology of MIF. J Clin Endocrinol Metab 70:8-10 18. Behringer RR, Cate RL, Froelick GJ, Palmiter RD, Brinster RL 1990 Abnormal sexual development in transgenic mice chronically expressing Mullerian inhibiting substance. Nature 345:167-170 19. Jost A 1991 Les peripeties d'une recherche: l'etude de la differentiation sexuelle. Med Sci 7:264-275 20. Jost A 1955 La biologie des androgenes chez l'embryon. In: Hie Reunion des Endocrinologistes de Langue Francaise. Paris: Masson, pp 160-180
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