HOFMEISTER, FRANZ

(b. Prague, Austria-Hungary [now Czechoslovakia], 30 August 1850; d. Würzburg, Germany, 26 July 1922)

Physiological chemistry, Pharmacology.

Hofmeister was named after his father, a wellrespected, prosperous physician in Prague; his mother’s maiden name was Anna Hess. During his medical studies at the German university in Prague, Hofmeister showed aptitude in chemistry and was advised by the physiologist Ewald Hering to work with Hugo Huppert, the newly appointed professor of applied medical chemistry. Huppert had been a student of Carl Gotthelf Lehmann, and specialized in clinical chemistry. Upon completing work for the medical degree in 1872, Hofmeister became an assistant in Huppert’s laboratory, and in 1879 received his Habilitation in physiological chemistry for work done there on peptones. The Prague medical faculty then decided to make Hofmeister head of a new institute for experimental pharmacology, so he had to obtain (in 1881) a Habilitation in that subject. In 1883, after six months in Strassburg, where Oswald Schmiedeberg headed the leading German institute of pharmacology, Hofmeister was appointed ausserordentlicher Professor of pharmacology at Prague; two years later he was made ordentlicher Professor, and in 1887 pharmacognosy was added to his professorial title. In 1896 pharmacognosoy succeeded Felix Hoppe-Seyler as professor of physiological chemistry at Strassburg; he remained there until 1919, after the reversion of the city to French rule. His final years were spent in Würzburg, where he was appointed honorary professor of physiological chemistry. In 1891 he married Johanna Gröger.

In Huppert’s laboratory, Hofmeister showed that the sugar excreted in the urine during pregnancy is not glucose, as had been thought, but lactose. He also examined various analytical methods for the identification of amino acids and for the detection of proteins in biological fluids. He then conducted a series of studies on peptones, the products of the gastric digestion of food proteins. During the latter half of the nineteenth century, many physiologists believed that peptones were the immediate metabolic precursors of blood proteins. In 1882 Hofmeister showed that peptones largely disappear in the intestinal mucosa, but his evidence was not sufficient to disprove the so-called peptone theory; this came in 1901 with the discovery by Otto Cohnheim of the enzyme he named erepsin.

The experimental work for which Hofmeister is most remembered dealt with the precipitation of proteins by inorganic salts. Beginning in 1887, he and his students (Siegmund Lewith, Rudolf von Limbeck, and Egmont Münzer) published a series of papers in which they reported that different salts could be placed in a regular order with respect to their salting-out effect on proteins, the order remaining essentially the same for different proteins. This relationship later came to be known as the’ Hofmeister series’ or’ lyotropic series.’ Hofmeister noted that the effect of the acidic and basic components of different salts is essentially additive, and he recognized that the differences among them are a general function of their hydration. He did not use the terms’ anions’ and’ cations, ’ however; Svante Arrhenius’ theory of electrolytic dissociation was not widely accepted until the 1890’s. An important consequence of this systematic study of the salting-out phenomenon was Hofmeister’s use of ammonium sulfate (introduced into protein chemistry by Camille Méhu in 1878) to effect the crystallization of egg albumin; this approach to the purification of proteins was actively pursued in his Strassburg laboratory: in the crystallization of human serum albumin (Hans Theodor Krieger, 1899) and of the Bence-Jones protein (Adolf Magnus-Levy, 1990), in the isolation of thyroglobulin (Adolf Oswald, 1899), and in the demonstration by Otto Porges and Karl Spiro (1903) that at least three types of globulins are present in human serum. Further work on the physical chemistry of proteins was largely conducted by Spiro; among his important publications in this field was one in 1914 (with Max Koppel) on buffers. Initially an organic chemist, Spiro became a pharmacologist, and then was associated with Hofmeister until they both left Strassburg in 1919.

In 1902, at the Karlsbad meeting of the Gesellschaft der Deutscher Naturforscher und Ärzte, Hofmeister delivered a plenary lecture on the structure of proteins. This was also the subject of his lengthy review article that appeared shortly afterward in Ergebnisse der Physiologie. After considering various earlier proposals, Hofmeister presented several arguments in favor of the view that, in proteins, the amino acid units are joined largely by amide bonds. He attached special significance to the biuret reaction, a color test given by proteins, peptones, and glycine derivatives that had been synthesized during the 1880’s by Theodor Curtius. He also cited, in support of his theory, physiological studies on the enzymatic cleavage of proteins and of hippuric acid. At the Karlsbad meeting the renowned organic chemist Emil Fischer, who had recently entered the protein field, espoused the same theory of protein structure, and gave the name“peptide” to the compounds formed by the linkage of amino acids through amide bonds. In subsequent accounts of the history of protein chemistry, these two lectures mark the appearance of the so-called Fischer-Hofmeister peptide theory of protein structure. This theory received strong support from Fischer’s extensive work between 1903 and 1909 on the chemical synthesis of peptides, but his success fell short of his hope to synthesize a natural protein.

Although Hofmeister is best known for his personal research and writings on proteins, he also concerned himself with other major biochemical problems. Among them was the question of the role in intracellular metabolism of enzymes, the term given by Wilhelm Friedrich (Willy) Kühne in 1876 to socalled unorganized or soluble ferments such as pepsin. Hofmeister worked in Prague on the newly discovered process of biological methylation and on the chemical pathway of biological urea formation: in 1901 he published a book on the chemical organization of the cell, and discussed the integration of enzyme action in metabolic processes. By that time, many intracellular enzymes had been identified, although some prominent physiologists (for example, Max Verworn and William Dobinson Halliburton) still adhered to the opinion that cellular respiration and biosynthesis are the expression of the activity of a protoplasm no t susceptible to chemical dissection. Hofmeister’s 1901 book may therefore be considered to reflect the emergence of a modern biochemistry based on the enzyme theory of life. It should be noted, however, that in 1914 Hofmeister wrote another article in which he modified his views in line with the current ideas about the colloidal nature of living matter.

After 1900 Hofmeister made no personal experimental contributions to the subject of his 1901 essay. but during the succeeding decade his junior associates at the Strassburg institute did much important work in this field. From their subsequent accounts it is evident that Hofmeister played a large role in suggesting problems and in guiding the research. Perhaps the greatest single success was the discovery (1904) by Franz Knoop of the β-oxidation pathway for the metabolic breakdown of fatty acids, shortly afterward (1908) Ernst Friedmann extended Knoop’s work to the study of the metabolic breakdown of the carbon chains of amino acids and of the formation of ketone bodies in this process. Other notable achievements included perfusion experiments on carbohydrate metabolism (1904) performed by Gustav Embden and the discovery of aldehyde mutase (1910) by Jacob Parnas; both men later became leaders in the elucidation of the so-called EmbdenMeyerhof-Parnas pathway of carbohydrate breakdown in muscle. Among the more important enzyme studies were also those of Otto von Fürth on tyrosinase (1902) and of Julius Schütz on the kinetics of pepsin action (1900). In addition to these contributions, significant work was done on other biochemical problems;especially noteworthy are Fürth’s study of adrenaline (1903), the work of Friedrich Bauer on the structure of inosinic acid (1907), and the discovery by Wilhelm Stepp of what later came to be called fat-soluble vitamin A (1909). From 1914 to 1918, Hofmeister contributed to the German war effort through such studies as an investigation of the nutritional value of army bread. He also began personal research on vitamins, and his final publications dealt with the purification of the anti-beriberi factor.

The productivity of Hofmeister’s Strassburg institute, especially during the years 1900 to 1910 attests to his role in the development of modern biochemistry and his influence on many young people who were to achieve distinction in the medical sciences. The Germans or Austrians included not only biochemists (Franz Knoop. Gustav Embden, Ernst Friedmann, Otto von Füth, Wilhelm Stepp), but also pharmacologists (Otto Loewi, Ernst Peter Pick, Alexander Ellinger, Walter Siegfried Loewe), the physiologist Albrecht Bethe, and several clinical investigators (Friedrich Kraus, Gustav von Bergmann. Adalbert Czerny, Adolf Magnus-Levy, Hans Eppinger, and Ernst Freudenberg). There were also many foreign guests, most of them from Japan, Italy, and Russia; in addition to Jacob Parnas from Poland, they included Lawrence J. Henderson from the United States and Henry Stanley Raper from Great Britain, Moreover, in the face of the tension between the German rulers and the French population of Alsace, Hofmeister won the affection of his Alsatian students and made special efforts to promote their interests, Among them were Léon Blum and Gustave Schickeleé. who after 1918 became professors of medicine and of obstetrics and gynecology, respectively, at Strassburg.

In 1901 Hofmeister founded the journal Beiträge zur chemischen Physiologie and Pathologie: Zeit-schrift für gesamte Biochemie. It ceased publication in 1908 when he decided to merge it with Bio-chemische Zeitschrift, established two years before by Carl Neuberg. Hofmeister’s journal included many important papers from his own and other biochemical laboratant.

From the foregoing it is evident that Hofmeister’s role as the leader of his research group was that of a senior counselor in the independent work of his junior associates on a great variety of scientific problems rather than that of the director of closely supervised teamwork along one. or only a few, lines of research identified with his name. This style of leadership was appropriate in the emergent field of biochemistry, whose many problems came largely from mammalian physiology. and where all available methods, including those of organic chemistry, physical chemistry, and biology, had to be applied to solve these problems. In this respect. Hofmeister imitated his predecessor Hoppe-Seyler, whose laboratory provided the seedbed for the subsequent development of physiological chemistry in many countries.

Hofmeister’s personal ambitions appear to have been modest. He had a happy family life and. until shortly before his death, enjoyed good health; there were leisure hours spent in doing watercolors or listening to music. A gracious Austrian, brilliant in conversation. Hofmeister also appears to have been at root a solitary person who regarded the world around him with skepticism, and often with scorn. He seems to have avoided scientific meetings, except when he was invited to present a lecture. He received few public honors, and sought none. Hofmeister’s greatness lay not only in his personal research achievements but even more in the fact that, given the opportunity to head an important center of biochemical research, he chose to further his discipline through the education of the next generation of its leaders.

BIBLIOGRAPHY

I. Original Works, A list of publications from Hofmeister’s laboratories is appended to the biographical memoir by J. Pohl and K. Spiro, ’ Franz Hofmeister: Sein Leben und Wirken.’ in Ergebnisse der Physiologie, 22 (1923), I–50. Among Hofmeister“s scientific articles, of special interest are: Zur Lehre von der Wirkung der Salze, II. Uber Regelmassigkiten in der eiweissfallenden Wirkung der Salze und ihre Beziehung zum physiologischen Verhalten derselben,” in Archiv für experimentelle Pathologie und pharmakologie. 24 (1888), 247–260;“Uber die Darstellung von kristallisiertem Eieralbumin und die Kristallisierbarkeit kolloider Stoffe,” in Zeitschrift f¨f physiologische Chemie14 (1890), 165–172; Die chemische Organisation der Zelle (Brunswick, 1901);’ Uber Bau und Gjruppierung der Eiweisskörper, ’ in Ergebnisse der physiologie, 1 (1902), 759–802; and Uber qualitativ unzureichende Ernährung, ’ lbid., 16 (1918), I–39, 510–589.

II. Secondary Literature. The most important available source of biographical information is the article by Pohl and Spiro (above). Other obituary notices include those by Karl Spiro, in Archiv für experimentelle Pathologie und Pharmakologie, 95 (1922), i–vii; and by Gustav Embden, in Klinische Wochenschrift, 1 (1922), 1974–1975. See also John Leo Abernethy, ’ Franz Hofmeister: The Impact of His Life and Research on Chemistry, ’ in Journal of Chemical Education, 44 (1967), 177–180; and Joseph S. Fruton, ’ Contrasts in Scientific Style. Emil Fischer and Franz Hofmeister: Their Research Groups and Their Theory of Protein Structure, ’ in Proceedings of the American Philosophical Society, 129 (1985), 313–370.

Joseph S. Fruton