The Discovery of Heparin Revisited: The Peptone Connection

THE DISCOVERY OF HEPARIN REVISITED: THE PEPTONE CONNECTION JAMES A. MARCUM* Adolf Schmidt-Muelheim is not considered the discoverer of heparin, a potent anticoagulant used routinely in hospitals to regulate thrombosis in patients. William H. Howell, the first professor of physiology at the Johns Hopkins School of Medicine, and his student Jay McLean, are generally recognized for this discovery, altiiough which ofthe two should be properly credited for the discovery of heparin used today has stirred some controversy [1, 2]. For example, Howell claimed that the anticoagulant isolated by McLean in 1916, a phosphatide, is not the same one isolated by him in 1922, a polysaccharide [2]. To reconstruct fully the discovery of heparin, however, requires the analysis of the work of Schmidt-Muelheim and others , in die late 1800s, on the phenomenon of peptone shock. By situating the work of Howell and McLean in a larger context that includes the anticoagulant phenomenon associated with peptone shock, the issue ofpriority concerning the discovery of heparin can be examined from a more complete perspective. Peptone Shock While working at Leipzig in the laboratory of the German physiologist Carl Ludwig, Schmidt-Muelheim published, in 1880, an article in which he described the effects of the intravenous injection of Witte's peptone, on the circulatory system [3] . The reason for injecting peptones into the circulatory system of an animal was to examine the means by which digestion products are assimilated into the body. Peptones were "thought to represent the intermediates in the metabolic conversion of dietary proteins into The author wishes to thank Dr. Ronald Anderson for his careful reading of the manuscript and for his many insightful comments; Dr. Allan Franklin for clarifying issues concerning the priority ofscientific discovery; and Dr.Joseph Fruton for drawing attention to historical examples of 19th- and 20th-century biochemistry. *Department of Biology, Houghton College, Houghton, NY 14744.© 1996 by The University of Chicago. All rights reserved. 0031-5982/96/3904-0941$01.00 610 James A. Marcum ¦ The Discovery ofHeparin blood proteins, for it seemed 'wasteful' for an animal organism to carry the breakdown of dietary proteins all the way to their constituent amino acids" [4, p.42]. Besides die rapid onset of vascular hypotension, Schmidt-Muelheim reported diat injection of peptones into the circulatory system of dogs also results in a marked incoagulability of the blood, when compared to blood taken from animals not injected with peptones. The anticoagulant phenomenon was achieved with ~0.3 gram of peptone per kilogram of body mass, although the phenomenon was not always reproducible. Similar findings were published contemporaneously, in summary form, by Pietro Albertoni [5] . In die following year, Giulio Fano, also working in Ludwig's laboratory , corroborated the finding that peptones induce the anticoagulant phenomenon [6]. After the initial observations ofthese earlier researchers, investigation into the anticoagulant property ofpeptones became an industry : "At die present [1905] this is die most thoroughly investigated field of blood coagulation" [7, p.98]. Schmidt-Muelheim was not, however, the first person to inject protein into the circulatory system of an animal and to observe an effect upon die coagulability of blood. In a series of lectures on the blood, delivered at the College of France in 1837-1838, Francois Magendie reported as well as demonstrated to an audience that injection of serum or egg whites into the circulatory system of a dog results in incoagulable blood: "You remember on a former occasion we found that injections of serum into the veins rendered the blood incoagulable ... on the cause of this animal's death (die one who died from the injection of whites of eggs into its veins); whether the blood was liquefied or not, can only be decided by autopsy, to which we now proceed. The very first incision that I make shows that the blood is in a fluid state" [8, p.245]. However, the result was not always reproducible, causing Magendie to note tiiat "this contradictory fact only serves to teach us how utterly ignorantwe are ofthe physiology ofthe blood, even where we fancy we are most thoroughly well informed" [8, p.247]. He also reported that addition of egg whites to blood removed from die body does not...