Polish archives of internal medicine | 2021
Erythropoietin: a story of a discovery with Polish contribution.
Abstract
317 Chaterine Walcott from Cornell University Medical College, New York, proved that anemic serum was triggering a “significant reticulocytosis” in the test animals.4 Five years later, 2 Finnish researchers, Eva Bonsdorff and Eeva Jalavisto, working at the University of Helsinki, interested in the red blood cell production mechanism, named the hemopoietic substance erythropoietin.5 In 1953, Danish-born Allan Erslev summarized the results of the experiments on animals and concluded: “Large amounts of plasma from rabbits, rendered anemic by bleeding, were injected into normal rabbits. A significant rise in the number of reticulocytes was observed in these rabbits.”6 Simultaneously, more evidence demonstrated that the hypoxic stimulation of erythropoiesis was an effect of the indirect humoral mechanism.3 Kurt Reissman, in an experimental model, used 2 parabiotic rats with direct connection of their blood circulatory systems at the capillary level. The first animal was kept in conditions of inducted hypoxia, while the other, in normal atmospheric environment. Both rats developed characteristic sings of reticulocytosis and increased hemoglobin. Bone marrow hyperplasia was also present. These results led Reissman to the conclusion that there must be some “humoral factor elicited by the hypoxemia in the one partner and transferred to the other one.”7 At the same time Gerhard Ruhenstroth-Bauer became seemingly convinced of the humoral regulation and published 2 papers in German in 1950 and 1952.8,9 That opened questions on the real nature of erythropoietin (EPO) and the possible place or places where it is produced. The first important reports were published in 1957. Leon Jacobson and his coworkers informed that bilaterally nephrectomized animals, subjected to bleeding, failed to In 2008, the history of erythropoietin research was presented among the most important discoveries in the special American Society of Hematology Anniversary Brochure, 50 Years in Hematology: Research That Revolutionized Patient Care. Erythropoietin (EPO), a 35-kDa glycoprotein, is the physiologically obligatory growth factor for erythroid development. Erythropoietin exerts its erythropoietic action by binding to the specific high-affinity cell surface receptor (EPOR) expressed on erythroid progenitor and precursor cells in the bone marrow. In adults, EPO is predominantly produced in the kidney by peritubular cells. Renal EPO production is under the control of an oxygen-sensing mechanism involving transcriptional regulation by hypoxia-inducible factor. Plasma EPO levels are measurable by a clinically available enzyme-linked immunosorbent test. But what is the story behind it? In the last decade of the 19th century and the first years of the 20th century, the hypoxia phenomenon began to be associated with the rate of red cell production. Although some hypotheses were formulated, for example, by Friedrich Miesner1 and Paul Carnot,2 no clear explanation for this relationship was then proposed. However, it should be noted that it was Carnot who came up with the idea that humoral regulation is responsible for the production of red blood cells and the active, still hypothetical, factor located in serum was named hemopoietin (hémopoïétine). But it was not earlier than in the 1940s and then 1950s that the next major steps were taken on the experimental level, showing that when anemic serum was injected in healthy rabbits, the induction of new red cell production occurred within 3 to 6 days.3 In 1943, Newton Krumdieck and MEMORIAL ARTICLE