Loeffler (Löffler), Friedrich August Johannes

(b. Frankfurt an der Oder, Germany, 24 June 1852;d. Berlin, Germany, 9 April 1915)

microbiology, medicine,

Loeffler’s father, Gottfried Friedrich Franz Loeffler, was a distinguished physician who rose to the rank of Generalarzt in the Prussian army. He wrote books on military medicine and from 1867 until his death in 1874 was assistant director of the Friedrich Wilhelm Institut for military doctors in Berlin, where he did much to raise the status of army medical officers. With this advantage the younger Loeffler began his own studies at the French Gymnasium of Berlin and became fluent in French, an important skill for those who were then pursuing microbiology. He attended the medical school of the University of Würzburg before transferring to his father’s school just before the Franco-Prussian War. After serving as a hospital assistant in that conflict, he was awarded the medical degree in 1874. Loeffler then became assistant physician at the Charité Hospital in Berlin, where for a year and a half he came in contact with some of the best clinicians of the time. From 1876 to 1879 he served as military surgeon and public health officer in Hannover and Potsdam, and in October 1879 he was assigned to the newly established Kaiserliches Gesundheitsamt in Berlin.

The assignment proved to be the turning point of his career. Nine months later Robert Koch arrived to set up a bacteriological laboratory, which, modest at first, soon became a leading center of research and discovery. Already famous for his work on anthrax, the development of a solid medium for cultivating bacteria, and a monograph on wound infection, Koch chose Loeffler and Georg Gaffky as his assistants. The next four years were to be highly productive for all the members of Koch’s group. As Loeffler later recalled:

The memory of those days, when we still worked in this room, Koch in the center and we about him, when almost daily new wonders in bacteriology arose before our astounded vision, and we, following the brilliant example of our chief, worked from morning to evening and scarcely had regard to our bodily needs—the memory of that time will remain unforgettable to us. Then it was that we learnt what it means to observe and work accurately and with energy to pursue the problem laid before us [in F. Nuttall, “Biographical Notes” 235].

During Loeffler’s four years at the imperial health office laboratories he pursued a number of bacteriological problems, including a series of experiments to determine effective means of disinfection. A significant practical result of these studies was the identification of the infectious agent of glanders, a disease seen mainly in horses. With the identification of the bacterium came the practical consequence of prevention. Although several others had described the occurrence of microorganisms in cases of glanders, no positive identification of an etiological agent had been made.

As with most of Loeffler’s subsequent bacteriological work, the glanders studies were models of the new experimental methods and criteria as applied to bacteriology by Koch. Loeffler took materials from glanders nodules in the lung and spleen of a horse and cultured them in test tubes containing blood serum. Here the bacteria were successfully grown in succeeding generations and then inoculated into a healthy horse, which began to show typical symptoms of glanders within forty-eight hours. At autopsy Loeffler found fresh nodules which again were productive of bacteria. He now clearly demonstrated them by staining with methylene blue. These bacteria, injected into rabbits, mice, and guinea pigs, produced the signs and symptoms suggestive of glanders. Bacilli cultivated from the small experimental animals, when injected into horses, produced the typical disease of glanders. Thus, in this sequence of experiments Loeffler satisfied the so-called Koch’s postulates, in 1882, the year Koch enunciated them: to isolate the organism, to grow it in pure culture, to infect experimental animals with the cultured organism, and then to again isolate the bacteria from the experimental animals.

Loeffler’s best-known work is the elucidation of the characteristics of the diphtheria bacillus and its growth in pure culture (1884), which again clearly revealed the imprint of Koch, with whom he was then so closely associated. For the first time bacteriologists could work with single microbial species even though the original specimen taken from the throat of a patient, for instance, might be teeming with myriads of organisms of different species.

Diphtheria, a disease known since antiquity, to the history of which Loeffler also devoted much time, was particularly feared because it produced a false membrane in the throat that could suffocate its victims, especially children. In 1871 Max Oertel, of Munich, showed that the false membrane could be produced in rabbits by swabbing their throats with secretions from human patients. In 1875 Edwin Klebs postulated a fungus as the cause, but at the German Medical Congress of 1883 Klebs presented new information pointing to a specific bacterium that could be seen, after staining, in the throat membranes of diphtheria patients. The task remained to differentiate the several bacteria that were implicated in the disease and to grow in pure culture the one responsible for causing it.

One of the difficulties Loeffler faced in isolating the agent of diphtheria was that the throats of diphtheria patients carried many microorganisms, one of which, the Streptococcus, had already led to much confusion. In a series of twenty-seven cases of fatal throat inflammation, twenty-two had been diagnosed as diphtheria, five as scarlatinal diphtheria. In the latter, Loeffler found that the Streptococcus was the dominant organism. It is now known that scarlet fever is accompanied or preceded by a streptococcal throat infection. In the case of diphtheria, Loeffler reasoned that these chains of cocci played a secondary role.

In the case of typical diphtheria Loeffler observed that the bacteria described by Klebs were easily demonstrated in about half the cases he studied. Loeffler found these bacilli, which stained markedly with methylene blue, in the deeper layers of the false membrane but never in the deeper tissues or other internal organs, although these organs may have been greatly damaged. Loeffler still had to culture both the Klebs bacillus, never grown before, as well as the Streptococcus to prove or disprove either one as the cause of diphtheria. The Streptococci were easily grown on the solid medium of peptone and gelatin devised by Koch. Inoculation into animals produced generalized infections but never a disease resembling human diphtheria.

The bacillus implicated by Klebs—and now strongly suspected by Loeffler as well—as the diphtheria-causing organism was difficult to culture on the usual gelatin plates because it would not grow at the low temperatures required to keep the gelatin solid. The Streptococci, on the other hand, grew well at temperatures below 24°C, needed to keep the medium from liquefying. At this point Loeffler’s innovative and experimental skills come out most clearly. He developed a new solid medium using heated blood serum rather than gelatin as the means of solidifying. This medium could now be incubated at 37°C, or body temperature. The Klebs bacilli grew well under these conditions. When they were injected into animals, Loeffler found that the guinea pig developed tissue lesions very similar to those of human diphtheria. Bacilli could be easily recovered from the infection produced at the site of inoculation, but they were never recovered from the damaged internal organs. Loeffler thus postulated that this, too, was similar to human diphtheria, in which the bacteria were confined to the throat membrane. He reasoned that perhaps the bacteria released a poisonous substance that reached other parts of the body through the bloodstream. This supposition was soon proved correct by the work of Émile Roux and Yersin, who did much to reveal the nature of the diphtheria toxin. In practical terms the toxin theory soon bore fruit in the work of Behring and others who developed an effective antitoxin to counter the effects of the soluble poison produced by the bacillus.

One further test carried out by Loeffler in this series of experiments to identify and isolate the agent of diphtheria was an attempt to culture the organisms from healthy children. Much to his surprise he was able to isolate the bacillus from one of the twenty subjects under study. He thereby called attention to the fact that not all people infected by the diphtheria bacillus or the tubercle bacillus had the disease diphtheria or tuberculosis. This concept of a healthy carrier had immense public health significance, especially in the period when medicine was making a headlong rush to ascribe all diseases to bacterial agents and when physicians too often simply equated the presence of a bacillus with a particular disease. The host factors thus had to come under study as well.

With the publication in 1884 of these wide-ranging studies of diphtheria, which in their process revealed not only the identifiable agent but the equally important phenomena of toxin production and the healthy-carrier state, Loeffler may be considered the principal discoverer of the diphtheria bacillus. He thus capped the findings of numerous clinical investigators of diphtheria and those of Klebs, who first observed the bacteria.

In 1884 Loeffler was transferred from the laboratory at the Gesundheitsamt to become director of the hygienic laboratory at the First Garrison Hospital in Berlin, where he continued his bacteriological studies and lectured on sanitation. At this time he discovered the cause of swine erysipelas and of swine plague. In 1886 he was appointed to the Faculty of Hygiene at the University of Berlin, and the following year, with his bacteriological colleagues, R. Leuckart and O. Uhlworm, he founded the Centralblatt für Bakteriologie und Parasitenkunde (later the Zentralblatt für Bakteriologie, Parasitenkunde, Infektionskrankheitenund Hygiene), one of the most influential journals in the field.

In 1888 Loeffler, renowned as a bacteriologist, researcher, and teacher, received calls to chairs in hygiene at the universities of Giessen and Greifswald. He accepted the latter offer and spent twenty-five years as a distinguished professor, serving as rector of the university from 1903 to 1907. In 1905 he was raised to the rank of Generalarzt in the army.

Early in his years at Greifswald, Loeffler began work on the problem of mouse typhoid and its bacteriological cause. Salmonella typhi-murium. This led to the first attempt to use bacteria for controlling the spread of an unwanted animal population, Pasteur had earlier suggested this be done to reduce the rabbit population in Australia, Having learned of Loeffler’s paper describing a new bacteriological method for controlling field mice, in 1892 the Greek government asked him to assist it with control of the rodents that threatened the harvests on the plain of Thessaly. In his laboratory studies Loeffler had shown that Salmonella typhi-murium was infectious for mice but not for other farm animals, and he planned to spread the disease among mice by contaminating their food sources. With Rudolf Abel, his assistant at the university, Loeffler journeyed to Greece in April 1892, After determining that the Thessalian vole was as susceptible to the bacteria as his laboratory animals, he began to culture huge quantities of the Salmonella necessary to spread in the fields. The dispersed bacteria killed many field mice, but there was some debate as to the real, practical effectiveness of Loeffler’s efforts at biological control. The subsequent realization that the bacteria may not be innocuous to man precluded further study.

In 1897 Loeffler became chairman of a German commission to investigate foot-and-mouth disease of cattle. The following year, working with his assistant, Paul Frosch, Loeffler made yet another fundamental discovery. The first real proof of the existence of a pathogenic organism so small that it was invisible under the microscope came from the work of Dmitry Ivanowsky, who in 1892 demonstrated its activity in tobacco mosaic. The first knowledge that these agents, known as filterable viruses because they passed through porcelain filters that stopped the larger bacteria, were also capable of causing disease in animals resulted from the work of Loeffler and Frosch (1898). They discovered that aphthous fever (foot-and-mouth disease) in cattle was caused by such a virus.

Lymph from infected animals, diluted and filtered so as to be entirely free of bacteria, produced the typical disease after injection into test animals. The question now was whether the lymph contained an effective toxin or a previously undiscovered agent. Loeffler and Frosch believed the latter possibility, that the activity of the lymph in causing further disease was due to an organism that could multiply yet was invisible with existing microscopes. Shortly after their work became known, William H. Welch in Baltimore called it to the attention of Walter Reed, who soon elucidated the viral nature of yellow fever and its transmission by mosquitoes.

Through his discoveries of several microorganisms as well as through his teaching and methods of work, Loeffler contributed greatly to the so-called golden age of bacteriology. Besides his improved culture media, bacteriological technique is also indebted to him for the popularization of the alkaline methylene blue stain as well as a specific stain for cilia and flagella. He introduced the standard medium for cultivation of the typhoid bacillus and improved the methods of isolating and differentiating the numerous fecal bacteria. He is also known for work on disinfect ion, hygiene of milk and water, and sewage disposal.

In 1913 Loeffler was recalled to Berlin to succeed Gaffky as director of the lnstitut für Infektionskrankheiten. He was active at the beginning of World War I in planning hygiene programs for the army. His health began to fail in December 1914, and despite surgical intervention he died on 9 April 1915. He was buried in Greifswald.

BIBLIOGRAPHY

I. Original Works. Loeffler’s memoir on the diphtheria bacillus is “Untersuchungen über die Bedeutung der Mikroorganismen für die Entstehung der Diphtherie,” in Mittheilungen am dem kaiserlichen Gesundheitsamt, 2 (1884), 421-499; see also “Berichte der Kommission zur Erforschung des Maul und Kanlenseuche,” in Centralblatt für Bakteriologie und Parasitenkunde,23 , Abt. I (1898), 371-391, written with Paul Frosch. His many other medical and bacteriological papers appeared mainly in the Mittheilungen am dem K. Gesundheitsamte, the Deutsche medizinische Wochenshrift, and the Centralblatt für Bakteriologie. One of the first books dealing with the history of bacteriology was his Vorlesungen über die geschichtliche Entwicklung der Lehre von den Bacterien (Leipzig, 1887).

Loeffler’s papers available in English trans, are “On the Bacillus of Glanders”; “Investigations as to the Significance of Microorganisms in the Production of Diphtheria in Man”; and “Disinfection by Steam,” written with R. Koch and G. Gaffky, in W. Watson Cheyne, ed., Recent Essays by Various Authors on Bacteria in Relation to Disease (London, 1886); and “The History of Diphtheria,” in G. H. F. Nuttall and G. S. Graham-Smith, eds., The Bacteriology of Diphtheria(Cambridge, 1908), pp. 1-52.

II. Secondary Literature. The following works (listed chronologically) contain useful biographical data; F. Goldschmidt, “Die Begründer der modernen Diphtheriebehandlung,” in Münchener medizinische Wochenschrift, 42 (1895), 335-336; and “Professeur Friedrich Loeffler” in Revue d’hygiène, 22 (1900), 652-655; G. Gaffky, “Friedrich Loeffler,” in Zentralblatt für Bakteriologie, Parasitenkunde, Infektionskrankheiten und Hygiene, 76 (1915), 241-245; George H. F. Nuttall, “Biographical Notes Bearing on Koch, Ehrlich, Behring, and Loeffler …,” in Parasitology, 16 (1924), 214-238; Dexter H. Howard, “Friedrich Loeffler and the Thessalian Field Mouse Plague of 1892,” in Journal of the History of Medicine and Allied Sciences,18 (1963), 272-281; and H. A. Lechevalier and M. Soltorovsky, Three Centuries of Microbiology (New York, 1965), pp. 122-136, 282-286.

Gert H. Brieger