Erythropoietin: A Somewhat Personal History

ERYTHROPOIETIN: A SOMEWHAT PERSONAL HISTORY EUGENE GOLDWASSER* The existence of erythropoietin (epo) —then termed "hemopoïetine" was postulated by Carnot and Dellandre, as long ago as 1906, but there were questions whether the experimental evidence was sufficient to indicate a humoral factor that could regulate the rate of red cell formation I. For more than 30 years the field of study of epo was largely in eclipse. Of the 40 years between the reemergence of the field in the 50s and the present, the years until 1987 could be described as a lag period, preceding the present -day exponential rise in both widespread interest and publications on epo. This later period, the time after the cloning and expression of the human epo gene, has seen the field become full-fledged with respect to therapeutic use, marketing, and patent litigation. It also has been a time of important advances in the study of the molecular and cellular biology of epo, its receptor, and of erythropoiesis. While this notable expansion in research is still in process, it seemed appropriate for me to agree with the suggestion of the editor of Perspectives to write a personal account of my experience that spans the period when epo was considered to be a laboratory curiosity (if it had any existence at all) to the present. The following students, postdocs, colleagues, and technicians representing 10 countries were all important contributors to the work from this laboratory, in addition to those mentioned in the text: P. Alibali, M. Barcos, J. Baron, D. Bedard, N. Beru, S. Chang, A. Dahlberg, Y. Dong, M. Dordal, P. Dukes,J. Eliason, O. Gallien-Lartique, A. Gardner, M. Gross, M. Gupta, C.Gurney, O. Hermine, M. Hrinda, G. Inana, S. Krantz, C. Lacombe, T. Lappin.J. McDonald, R. Meints, E. Morris, P. Mungai, W. Nijhof, N. Pech, R. Pine, I. Rich, K. Sahr, D. Schlesinger, D.Sikkema, D. Smith, P. Storring, F. Takaku, K. Taylor, B. Tong, C. Truit, G. Van Zant, F. Wang, W. White. This laboratory is now supported by Grants HL21676 and HL30121 from the National Heart, Lung, and Blood Institute. Mrs. Betty Kniaz provided invaluable, patient, secretarial service for this paper. *Department of Biochemistry and Molecular Biology, The University of Chicago, Cummings Life Science Center, 920 East 58th Street, Chicago, IL 60637.© 1996 by The University of Chicago. All rights reserved. 0031-5982/96/3904-0976101.00 18 Eugene Goldwasser ¦ Erythropoietin Early History Although the earliest history of epo is most assuredly not within my personal experience, it seems that this essay might be a good place to set some of the record straight with regard to who did what and when. The original published observations of Carnot and Deflandre, indicating that there was a humoral factor that mediated the response to anemic hypoxia by causing an increase in red cells 1, followed a long history of observation on the response to high-altitude hypoxia and of regeneration of blood after loss (for a review ofthis early work see 2 ) . The Carnot feedback loop hypothesis was not generally accepted, partly because of the inability ofsome investigators to confirm the experimental results and partly, I surmise, because of the conventional wisdom that hypoxia acted directly on the blood-forming system, rather than causing the formation of a plasma factor which acted on the bone marrow. There was, however, at least one early paper that lent some credence to the Carnot mechanism. Förster and Kiss did an experiment similar to that of Carnot and Deflandre and measured red cell number , as did Carnot, without seeming to recognize the statistical pitfalls of that method 3 . They found a slightly greater average rate of red cell regeneration in bled rabbits treated with anemic plasma than in controls. When it became feasible to use reticLilocyte counts as the end point, the Carnot mechanism was supported by evidence provided by Krumdieck, and later by Reissmann and Ruhenstroth-Bauer 4-6. Both of these latter investigators used a parabiotic rat model to show the presence of a bloodborne factor that was formed as a result of hypoxic stress to one of the pair of parabiotic animals and that caused increased red cell formation in...