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Ray Owen: A tribute
Cellular Immunology 299 (2016) 3–5
Contents lists available at ScienceDirect
Cellular Immunology journal homepage: www.elsevier.com/locate/ycimm
Editorial
Ray Owen: A tribute
It seems extraordinary that 70 years have gone by since Ray D. Owen gave birth to the notion of immunological tolerance when he published his seminal 3-page paper in Science [1]. Even more extraordinary is the fact that the concept of tolerance is still a live topic that is much discussed at international conferences, and that attempts to bring this concept into the clinic continue to this day. Although clinical tolerance has already been demonstrated by several groups, a method of achieving tolerance in organ transplant recipients that can be applied routinely and safely has yet to be devised. The ONE Study, currently being carried out by a consortium of European and American transplant centers, in which the safety and efficacy of several kinds of immunoregulatory cells are being compared, is the latest such attempt. The fact that the methods employed differ starkly from those described by Owen as occurring naturally in cattle twin fetuses and experimentally by Billingham, Brent & Medawar in their analytical studies in mice and chickens, is neither here nor there. So what was Ray Owen’s vital contribution? In his brief Science paper he showed that cattle fraternal twins almost invariably display red blood cell chimerism. To his surprise he found that adult fraternal twins possess two kinds of red blood cells: those patently derived from their own bone marrow, and others that bore the phenotype of their twin partner. This puzzling situation was resolved by Owen’s knowledge of F.R. Lillie’s much earlier finding that cattle dizygotic twins usually develop an anastomosis of their placentae, thus facilitating the free circulation of blood from one http://dx.doi.org/10.1016/j.cellimm.2015.12.001 0008-8749/Published by Elsevier Inc.
fetus to the other (Fig. 1). This allowed Owen to speculate that the presence of the foreign blood cells had induced a state of unresponsiveness in their foreign hosts, and that this unresponsiveness – later in 1948 coined as ‘‘tolerance” by Burnet and Fenner – persisted into adult life, presumably as a result of a profound change in the host’s immune system that permitted the foreign cells to persist. Owen wrote that ‘‘Several interesting problems in the fields of genetics, immunology and development are suggested by these observations”. Whilst Owen must therefore be regarded as having recognized tolerance as a fundamental phenomenon he did not pursue this notion further, and it was left to Medawar and his colleagues to study the phenomenon experimentally and in depth in experiments involving inbred strain of mice and in chickens. Strangely, Medawar and his colleagues entered this field quite independently although they derived a crucial insight from Owen’s observations. In 1950 they embarked on a study devised to distinguish between cattle mono- and dizygotic twin calves, Medawar having been asked to find a solution to the problem because of its importance in cattle farming, for the female partner of a male twin was always sterile and the sex of young calves could not be established reliably by morphological means. Medawar therefore postulated that monozygotic twins would accept each other’s skin grafts but that dizygotic twins would reject them. In retrospect it seems like an interesting academic exercise but hardly a method that could be widely applied in agriculture! However, his team found to their puzzlement that both types of twins usually fully accepted their partners’ grafts. It was only when they became aware of Owen’s findings, which had been highlighted in Burnet and Fenner’s wide-ranging and speculative 1948 monograph on ‘‘The Formation of Antibodies” [2], that Medawar’s group understood why they had obtained these contradictory results. As cattle dizygotic twins had been shown to be red blood cell chimeras, the unresponsiveness they had developed to each other’s blood cells evidently extended also to skin, suggesting that the red cell precursors that had induced the immunological change must have carried the same cellular antigens present on skin cells. It is arguable whether and how soon Medawar’s group would have recognized the basis of their findings, but there is no doubt at all that their knowledge of Owens’s findings led them to a formulation of a general theory of immunological tolerance and to their analytical studies first published in Nature in 1953 [3] and fully presented in their hallmark 1956 Phil. Trans. B publication – one that the Royal Society recently identified as one of the 17 most influential biological papers published in the 350 years of the Society’s history.
4
Editorial / Cellular Immunology 299 (2016) 3–5
Fig. 1. Cartoon depicting the breeding of dizygotic cattle and recognition by Ray Owen of the basics of immunologic tolerance due to exchange of blood cells in utero. (Courtesy of Dr. R.D. Owen.)
And so Ray Owen and Peter Medawar’s group at University College London became inextricably linked. Indeed, Owen readily provided the UCL group with anti-red blood cell antisera that helped them in their chicken experiments to distinguish between the red blood cells in both experimentally induced and naturally occurring red cell chimeras, in which crucially they also showed the full acceptance of skin grafts of twin partners. It was the demonstration that tolerance could be induced to skin grafts (and later kidney grafts) that the importance of the phenomenon of tolerance became fully recognized. Most scientific discoveries have some sort of antecedent. The astonishing feature of Owen’s discovery was that there was none whatever. His observations came entirely out of the blue and marked the beginning of a new field of endeavor in immunology and transplantation research. Medawar and Burnet were to share the 1960 Nobel Prize in Medicine and Physiology; Owen’s seminal contribution was unfortunately overlooked. One can only speculate as to the reasons for this – possibly it was held against him that he had not more fully explored his initial findings. In any event, in a letter sent to Owen in 1960, Medawar expressed his regret that Owen had not shared the prize, and Owen responded typically, in the most generous and gracious terms. It was thanks to the contact between Owen and Medawar that I joined Owen’s department at Caltech in 1956 for a year as a Rockefeller Research student – a year in which a durable friendship was forged between them. Many years later Owen wrote two memorable and generous Forewords to Brent’s ‘‘A History of Transplantation Immunology” [4] and to his autobiography ‘‘Sunday’s Child? A Memoir” [5].
So, what kind of a man was Ray Owen, who died at the age of 98 in 2014? He was born on a dairy farm in Genesee, Wisconsin, where after school he often helped with the milking of cows. Indeed, all his formative years were spent in Wisconsin, which was ‘‘home” to him until he became a true Californian. He obtained a B.Sc. in genetics at Carroll College and proceeded from there to the University of Wisconsin, where he studied genetic markers, principally in cattle, in Malcolm Irwin’s department of Immunogenetics. Together with Clyde Stormont he embarked on a study on the inheritance of red blood cell antigens in cattle, and it was in the course of these studies that he made his astonishing discovery – a discovery that, though published in Science in 1945, was totally ignored by the immunological community until Burnet and Fenner gave it their attention in their 1948 monograph and Medawar’s group underlined its huge importance. The Czech biologist Milan Hašek too had made some observations in the early 1950s, which, although misinterpreted by him initially, were consonant with the principles of immunological tolerance. It was at the University of Wisconsin that Ray met his future wife and lifelong partner, June Weissenberg – a charming, highly intelligent and socially deeply committed woman – and together they moved to Pasadena in 1946. Ray had been offered a senior post at Caltech, and soon became head of the Biology Division. He presided over this with a light hand and made his mark in more ways than one – as an experimental scientist and as administrator and teacher. Although he published a great many papers in genetics and immunology, his main contribution was, arguably, the mentoring of many Ph.D. students and post-doctoral Fellows, many of whom were to make their mark in the field of immunogenetics. He was much loved by them as a generous and well-read mentor as
Editorial / Cellular Immunology 299 (2016) 3–5
well as a man, and his 80th and 90th birthday celebrations, attended by many of his former students as well as by senior immunologists, were wonderfully warm occasions. In 1996 the University of Wisconsin, his alma mater, organized a symposium on ‘‘Fifty Years of Tolerance” in his honor, and this proved to be a unique international gathering of those working in the field. (Medawar was unable to attend because, a few years earlier, he suffered from a calamitous stroke.) Not surprisingly, Owen has gone on record to say that he counted his interaction with students among his greatest satisfactions. This volume, dedicated to Ray, is proof of the high regard his former students still have for him. Owen’s other huge contribution to the life of Caltech was as Dean for Undergraduate Students. This time-consuming responsibility involved not only the counseling of students, but also lengthy trips to other parts of the United States, to recruit undergraduate students of the highest caliber. He was without doubt a jewel in the institution’s crown, and this was recently acknowledged by a celebration at Caltech of Ray’s life and scientific contribution. Although the Nobel Prize eluded him, Ray Owen received a great many honors and prizes. Among these were the Gregor Mendel Medal, The Thomas Hunt Morgan Medal of the Genetics Society of America, and the Peter Medawar Medal and Prize of The Transplantation Society. He was also honored by several honorary doctorates, Despite all this recognition Ray remained a genuinely modest man – genial, approachable and knowledgeable. I spent a year with Ray (1956–7) remembers him sitting in his office, his desk laden with books and journals, smoking his pipe and drinking a cup of
5
his beloved tea that he brewed at regular intervals. Had it not been for his colorful Californian shirts he might have passed as a typical Englishman! He was, indeed, proud of his Welsh (not English!) ancestry. He had a happy marriage to June, who pre-deceased him by just a year. He is survived by his older son, David, and remembered by the members of his ‘‘tree” and their trainees. He would be embarrassed by these tributes. Acknowledgment The author is grateful to Prof. E. Simpson for her comments on this manuscript. References [1] R.D. Owen, Immunogenetic consequences of vascular anastomoses between bovine twins, Science 102 (2651) (1945) 400–401. [2] F.M. Burnet, F. Fenner, The Formation of Antibodies, Macmillan Press, Melbourne, 1948. [3] R.E. Billingham, L. Brent, P.B. Medawar, ‘Actively acquired tolerance’ of foreign cells, Nature 172 (1953) 603–606. [4] Leslie B. Brent, A History of Transplantation Immunology, Academic Press, San Diego, 1997, ISBN 0121317706. [5] Leslie Baruch Brent, Sunday’s Child? A Memoir, Bank House Books, New Romney, UK, 2009, ISBN 9781904408444.
Leslie Brent University of London, London, England, United Kingdom
Contents lists available at ScienceDirect
Cellular Immunology journal homepage: www.elsevier.com/locate/ycimm
Editorial
Ray Owen: A tribute
It seems extraordinary that 70 years have gone by since Ray D. Owen gave birth to the notion of immunological tolerance when he published his seminal 3-page paper in Science [1]. Even more extraordinary is the fact that the concept of tolerance is still a live topic that is much discussed at international conferences, and that attempts to bring this concept into the clinic continue to this day. Although clinical tolerance has already been demonstrated by several groups, a method of achieving tolerance in organ transplant recipients that can be applied routinely and safely has yet to be devised. The ONE Study, currently being carried out by a consortium of European and American transplant centers, in which the safety and efficacy of several kinds of immunoregulatory cells are being compared, is the latest such attempt. The fact that the methods employed differ starkly from those described by Owen as occurring naturally in cattle twin fetuses and experimentally by Billingham, Brent & Medawar in their analytical studies in mice and chickens, is neither here nor there. So what was Ray Owen’s vital contribution? In his brief Science paper he showed that cattle fraternal twins almost invariably display red blood cell chimerism. To his surprise he found that adult fraternal twins possess two kinds of red blood cells: those patently derived from their own bone marrow, and others that bore the phenotype of their twin partner. This puzzling situation was resolved by Owen’s knowledge of F.R. Lillie’s much earlier finding that cattle dizygotic twins usually develop an anastomosis of their placentae, thus facilitating the free circulation of blood from one http://dx.doi.org/10.1016/j.cellimm.2015.12.001 0008-8749/Published by Elsevier Inc.
fetus to the other (Fig. 1). This allowed Owen to speculate that the presence of the foreign blood cells had induced a state of unresponsiveness in their foreign hosts, and that this unresponsiveness – later in 1948 coined as ‘‘tolerance” by Burnet and Fenner – persisted into adult life, presumably as a result of a profound change in the host’s immune system that permitted the foreign cells to persist. Owen wrote that ‘‘Several interesting problems in the fields of genetics, immunology and development are suggested by these observations”. Whilst Owen must therefore be regarded as having recognized tolerance as a fundamental phenomenon he did not pursue this notion further, and it was left to Medawar and his colleagues to study the phenomenon experimentally and in depth in experiments involving inbred strain of mice and in chickens. Strangely, Medawar and his colleagues entered this field quite independently although they derived a crucial insight from Owen’s observations. In 1950 they embarked on a study devised to distinguish between cattle mono- and dizygotic twin calves, Medawar having been asked to find a solution to the problem because of its importance in cattle farming, for the female partner of a male twin was always sterile and the sex of young calves could not be established reliably by morphological means. Medawar therefore postulated that monozygotic twins would accept each other’s skin grafts but that dizygotic twins would reject them. In retrospect it seems like an interesting academic exercise but hardly a method that could be widely applied in agriculture! However, his team found to their puzzlement that both types of twins usually fully accepted their partners’ grafts. It was only when they became aware of Owen’s findings, which had been highlighted in Burnet and Fenner’s wide-ranging and speculative 1948 monograph on ‘‘The Formation of Antibodies” [2], that Medawar’s group understood why they had obtained these contradictory results. As cattle dizygotic twins had been shown to be red blood cell chimeras, the unresponsiveness they had developed to each other’s blood cells evidently extended also to skin, suggesting that the red cell precursors that had induced the immunological change must have carried the same cellular antigens present on skin cells. It is arguable whether and how soon Medawar’s group would have recognized the basis of their findings, but there is no doubt at all that their knowledge of Owens’s findings led them to a formulation of a general theory of immunological tolerance and to their analytical studies first published in Nature in 1953 [3] and fully presented in their hallmark 1956 Phil. Trans. B publication – one that the Royal Society recently identified as one of the 17 most influential biological papers published in the 350 years of the Society’s history.
4
Editorial / Cellular Immunology 299 (2016) 3–5
Fig. 1. Cartoon depicting the breeding of dizygotic cattle and recognition by Ray Owen of the basics of immunologic tolerance due to exchange of blood cells in utero. (Courtesy of Dr. R.D. Owen.)
And so Ray Owen and Peter Medawar’s group at University College London became inextricably linked. Indeed, Owen readily provided the UCL group with anti-red blood cell antisera that helped them in their chicken experiments to distinguish between the red blood cells in both experimentally induced and naturally occurring red cell chimeras, in which crucially they also showed the full acceptance of skin grafts of twin partners. It was the demonstration that tolerance could be induced to skin grafts (and later kidney grafts) that the importance of the phenomenon of tolerance became fully recognized. Most scientific discoveries have some sort of antecedent. The astonishing feature of Owen’s discovery was that there was none whatever. His observations came entirely out of the blue and marked the beginning of a new field of endeavor in immunology and transplantation research. Medawar and Burnet were to share the 1960 Nobel Prize in Medicine and Physiology; Owen’s seminal contribution was unfortunately overlooked. One can only speculate as to the reasons for this – possibly it was held against him that he had not more fully explored his initial findings. In any event, in a letter sent to Owen in 1960, Medawar expressed his regret that Owen had not shared the prize, and Owen responded typically, in the most generous and gracious terms. It was thanks to the contact between Owen and Medawar that I joined Owen’s department at Caltech in 1956 for a year as a Rockefeller Research student – a year in which a durable friendship was forged between them. Many years later Owen wrote two memorable and generous Forewords to Brent’s ‘‘A History of Transplantation Immunology” [4] and to his autobiography ‘‘Sunday’s Child? A Memoir” [5].
So, what kind of a man was Ray Owen, who died at the age of 98 in 2014? He was born on a dairy farm in Genesee, Wisconsin, where after school he often helped with the milking of cows. Indeed, all his formative years were spent in Wisconsin, which was ‘‘home” to him until he became a true Californian. He obtained a B.Sc. in genetics at Carroll College and proceeded from there to the University of Wisconsin, where he studied genetic markers, principally in cattle, in Malcolm Irwin’s department of Immunogenetics. Together with Clyde Stormont he embarked on a study on the inheritance of red blood cell antigens in cattle, and it was in the course of these studies that he made his astonishing discovery – a discovery that, though published in Science in 1945, was totally ignored by the immunological community until Burnet and Fenner gave it their attention in their 1948 monograph and Medawar’s group underlined its huge importance. The Czech biologist Milan Hašek too had made some observations in the early 1950s, which, although misinterpreted by him initially, were consonant with the principles of immunological tolerance. It was at the University of Wisconsin that Ray met his future wife and lifelong partner, June Weissenberg – a charming, highly intelligent and socially deeply committed woman – and together they moved to Pasadena in 1946. Ray had been offered a senior post at Caltech, and soon became head of the Biology Division. He presided over this with a light hand and made his mark in more ways than one – as an experimental scientist and as administrator and teacher. Although he published a great many papers in genetics and immunology, his main contribution was, arguably, the mentoring of many Ph.D. students and post-doctoral Fellows, many of whom were to make their mark in the field of immunogenetics. He was much loved by them as a generous and well-read mentor as
Editorial / Cellular Immunology 299 (2016) 3–5
well as a man, and his 80th and 90th birthday celebrations, attended by many of his former students as well as by senior immunologists, were wonderfully warm occasions. In 1996 the University of Wisconsin, his alma mater, organized a symposium on ‘‘Fifty Years of Tolerance” in his honor, and this proved to be a unique international gathering of those working in the field. (Medawar was unable to attend because, a few years earlier, he suffered from a calamitous stroke.) Not surprisingly, Owen has gone on record to say that he counted his interaction with students among his greatest satisfactions. This volume, dedicated to Ray, is proof of the high regard his former students still have for him. Owen’s other huge contribution to the life of Caltech was as Dean for Undergraduate Students. This time-consuming responsibility involved not only the counseling of students, but also lengthy trips to other parts of the United States, to recruit undergraduate students of the highest caliber. He was without doubt a jewel in the institution’s crown, and this was recently acknowledged by a celebration at Caltech of Ray’s life and scientific contribution. Although the Nobel Prize eluded him, Ray Owen received a great many honors and prizes. Among these were the Gregor Mendel Medal, The Thomas Hunt Morgan Medal of the Genetics Society of America, and the Peter Medawar Medal and Prize of The Transplantation Society. He was also honored by several honorary doctorates, Despite all this recognition Ray remained a genuinely modest man – genial, approachable and knowledgeable. I spent a year with Ray (1956–7) remembers him sitting in his office, his desk laden with books and journals, smoking his pipe and drinking a cup of
5
his beloved tea that he brewed at regular intervals. Had it not been for his colorful Californian shirts he might have passed as a typical Englishman! He was, indeed, proud of his Welsh (not English!) ancestry. He had a happy marriage to June, who pre-deceased him by just a year. He is survived by his older son, David, and remembered by the members of his ‘‘tree” and their trainees. He would be embarrassed by these tributes. Acknowledgment The author is grateful to Prof. E. Simpson for her comments on this manuscript. References [1] R.D. Owen, Immunogenetic consequences of vascular anastomoses between bovine twins, Science 102 (2651) (1945) 400–401. [2] F.M. Burnet, F. Fenner, The Formation of Antibodies, Macmillan Press, Melbourne, 1948. [3] R.E. Billingham, L. Brent, P.B. Medawar, ‘Actively acquired tolerance’ of foreign cells, Nature 172 (1953) 603–606. [4] Leslie B. Brent, A History of Transplantation Immunology, Academic Press, San Diego, 1997, ISBN 0121317706. [5] Leslie Baruch Brent, Sunday’s Child? A Memoir, Bank House Books, New Romney, UK, 2009, ISBN 9781904408444.
Leslie Brent University of London, London, England, United Kingdom