Monozygotic bovine quadruplets
H. P. DONALD, W. S. BIGGAR and D. M. LOGAN Animal Breeding and Genetics Research Organisation, Edinburgh Received Io.v.5o ON the 27th January 1949, a Friesian type cow called Peggy, and belonging to Mr William Youngs of Sankence Farm, Aylsham, Norfolk, produced four bull calves. After undergoing considerable publicity for a few days, Peggy died, but the calves survived and were purchased by the Agricultural Research Council, and transferred to the Cattle Breeding Research Farm at Cold Norton in Staffordshire. These calves are remarkable, not only because quadruplets are unusual in cattle, but also because they were born alive, and were all of the same sex. Furthermore, they appear to be the first recorded set judged to be of monozygotic origin. A somewhat detailed account of them, therefore, appears desirable. Unfortunately, two of the calves died a few weeks after purchase, so that a comparison of late developing features became impossible. The evidence on which the diagnosis of one-egg origin is based is as follows. Except where otherwise noted, all remarks apply equally to all four calves.
The Birth of Transplant Immunology.
Leslie’s PhD studies in the early 1950s produced what is probably the most important paper ever published in transplantation. What was known and what unknown about transplantation immunology at the time? Both of these questions can of course be answered only in retrospect. We can certainly now say that very little was known. Probably the main thing that was known with any level of certainty was that graft rejection was an immunologic response. The demonstration by Medawar of memory in the rejection of skin allografts in rabbits proved this point. Interestingly, it was a point that had been made quite well many years earlier by Georg Schöne. Schöne published his insightful paper entitled “Uber transplantationsimmunität” in 1912. The other thing that was well known was that suppressing the rejection of kidney grafts, both in man and experimental animals such as dogs, was impossible. Many authors had studied this intensively and had exhausted their ingenuity in their attempts to find a solution. As late as 1955, David Hume wrote “renal homotransplantation has no place in the therapy of human patients at this time.” He would only a few years later be a major player in establishing azathioprine as a key drug in launching kidney transplantation as a viable therapeutic procedure for chronic renal failure. One other thing in the background during Leslie’s studies was the brilliant work of Peter Gorer. He established, using tumor transplantation studies in inbred mice, that a single genetic locus was primarily responsible for inducing tumor rejection. This genetic locus was, of course, what turned out to be the H-2 locus, also known as the mouse major histocompatibility complex (MHC). But the huge complexity of that locus, the existence of MHC class II antigens and the definition of the human MHC (HLA) were all basic matters for the future. In these circumstances, a field relies on chance rather than careful theorizing. That chance came in 1945 when Ray Owen published his remarkable observation that the majority of 80 pairs of cattle twins had identical blood groups. This was in spite of the fact that some of the twins were of unlike sex, and many twins of the same sex were phenotypically clearly not monozygotic. Several blood groups had been evaluated, so the chance that the dizygotic twins shared all alleles by chance was vanishingly small. Owen recalled the studies of Lillie in 1916, who showed that the majority of dizygotic cattle twins were synchorial, that is, they shared a single placenta and therefore shared a single blood circulation in utero. This phenomenon is rare in other species. Owen correctly hypothesized that the sharing of hematopoietic precursors (stem cells) in utero resulted in the cattle twins each having 2 sets of blood cells—their own and that of their twin—for all of their lives. This was a remarkable example of the induction of graft tolerance. It formed the basis of Burnet and Fenner’s hypothesis that self tolerance was a consequence of the exposure of the immune system to self antigens in utero. However, very interestingly, it lay there largely unnoticed in the literature. The thing that fortuitously triggered interest in Owen’s paper was the difficulty of defining monozygosity and dizygosity in cattle twins. The fact that both monozygotic (identical) and dizygotic (fraternal) twins shared all blood groups meant that the standard approach of blood group typing was of no value. One had to rely on physical characteristics, such as color patterns and hair whorls. HP Donald suggested to Peter Medawar that he perform skin grafts between the cattle twins, expecting (incorrectly as history has shown) that the monozygotic twins would accept their twin’s skin graft while the dizygotic twins would reject them. As things turned out, both monozygotic and dizygotic twins completely accepted each other’s grafts! What nobody had anticipated at the time is that the life-long acceptance of blood precursors from the twin would also induce tolerance to a tissue graft such as skin. We now know that such hematopoietic chimerism induces profound tolerance to the tissues of the stem cell donor. From here, it was a small step to reproduce in the laboratory what they had observed in nature. They injected CBA strain mouse embryos at the 15th or 16th day of gestation with lymphoid and other tissues from the A strain. At 8 weeks of age, the normal looking CBA mice were given a strain skin grafts—and the majority showed complete tolerance. They accepted their skin grafts for life! At a bleak moment in the history of the clinical application of kidney transplantation, this study showed in a spectacular fashion that the spectrum of antigens that could be regarded as self was subject to experimental and therefore potentially to clinical manipulation to provide long-term graft acceptance. It sparked an absolutely huge amount of research over >50 years on transplantation tolerance. Received 19 February 2020.
Inheritance of Black and Red Coat Colors in Cattle.
TABLE OF CONTENTS PAGE INTRODUCTION.. .... ............................................................ 419 Source of Material.. ...................... ....................... 420 Hypothesis. .................................................................... 421 Presentation and discussion of data ....................... 421 S"RY AND CONCLUSIONS.. ..................................................... 427 LITERATURE CITED.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 427 APPENDur-Table 6. ............................................................ 428