Managing failure: Sir Peter Brian Medawar's transplantation research

Abstract

Sir Peter Medawar experimentally demonstrated immunological tolerance through his tissue transplantation experiment in the early and mid-1950s. He made a central contribution to modern biomedicine by showing that genetically distinct cells introduced into a body during its foetal phase could not only be permanently tolerated but also make the host accept any subsequent skin grafts from the original cell donors. However, this discovery had only a limited clinical applicability. None could practise Medawar's method on human foetuses in preparation for their future need for organ or skin transplantation. I analyse this problem by focusing on his management of ‘failures’ during the tissue transplantation experiments. Through statistical, material, theoretical and rhetorical strategies, he managed unsatisfactory findings of his research, including unexpected skin infection, sudden animal death and irregularities in homograft survival times. I argue that these strategies and their inherent ambiguities constituted the course of Medawar's research, enabling him to delineate the temporal dimensions of tolerance and a clinical relevance, which were mutually contradictory. This paper thus illustrates the multiple roles that failures play in scientific research as well as the conflicting outcomes of investigators' efforts to manage them.

Immunological Consequences of In Utero Exposure to Foreign Antigens

“…The conferment of skin tolerance in Medawar's experiment of a partially MHC-mismatched murine model was not an all-or-none event but rather a graded phenomenon (29) with test graft survivals varying from only a few days of grace beyond the median survival time to 1 month or longer. The graded phenomenon of skin tolerance was also observed following in utero transplantation of fully MHC-mismatched HSCs in mice (28,32,49), as evidenced by a wide variability of donor skin survivals, ranging from prolonged for a few days or weeks over their counterpart controls to persistent for more than 4 months, highly relevant to hematopoietic chimerism actually obtained (32,49,92).…”

“…In 2018, Medawar's work was illuminated from a distinctive perspective by Hyung Wook Park (29). It was found that Medawar did not publish the whole story of his experimental tolerance induction in murine fetuses.…”

“…It was found that Medawar did not publish the whole story of his experimental tolerance induction in murine fetuses. A review of Medawar's laboratory notes revealed that tolerance recorded as their donor skin survivals of over 1 month merely happened to 6 of 77 fetal recipients in 15 sets of experiments (a partially MHCmismatched model, Table 1), along with failure or breakdown of skin grafts at median survival time of 11 days in 56, survival for 12-14 days in 4, and for 15-30 days in 11 (29). The overall success rate was estimated at 7.8% (6/77), far much lower than formally reported in 1953 Nature manuscript (3 out of six murine fetuses, Exp.…”

Regulatory Macrophages and Tolerogenic Dendritic Cells in Myeloid Regulatory Cell-Based Therapies

“…Medawar’s earliest discovery (1953) showed that transferring regulatory cells from tolerant to naive animals resulted in significant tolerance to subsequent organ transplant. This phenomenon led other scientists to investigate the immune system’s discrimination between ‘self’ and ‘nonself’, and demonstrated a biological rather than chemical immunological affect [ 1 ]. Medawar showed that isolated splenocytes, kidney cells or testicular cells from adult mice could be intravenously infused into immunologically immature mice in utero or perinatally.…”