Adolpho Lutz and dermatology in historical perspective

Adolpho Lutz and dermatology in

historical perspective

 

Jaime Benchimol

In the early months of 1882, Adolpho Lutz settled down to work as a general practitioner in Limeira, in the interior of the State of São Paulo, Brazil. Limeira was an important center for the cultivation of coffee, sugarcane and cereals, and had a population of approximately four thousand inhabitants, including a sizeable Swiss-German colony. He soon wrote to a Swiss periodical in which he had

already described his life as a teacher and physician in Brazil. 1 He did not want to lose contact with European medicine, and he now described a plan he had in mind to study questions that might be important to his fellow physicians in the Old World.

He was interested in making "contributions to medical geography" by publishing studies on parasites, especially Ancylostoma duodenale, "if interest in these parasites has not already died down since the end of construction of St. Ghotard tunnel". In Limeira, Lutz (1883, p.30) came into contact with vast material on malaria and some rare cases of beriberi.

I have also been able to make a number of observations about

the influence of climate and race on various diseases. In my

office I see blacks and Brazilians, as well as Germans,

Portuguese and Italian immigrants who, together, comprise a

considerable diversity. They therefore provide very interesting

comparative material.

Although the relationships between climate, race and diseases was the topic that seemed most appealing to Europeans when Lutz was living in Limeira (June, 1882 to March, 1885), he also paid very close attention to the parasites that caused so much damage to his heterogeneous clientele and to the animals they had contact with. He would therefore broaden the repertoire of pathologies that Wucherer and other members of the Tropicalist School in Bahia had begun to investigate (Coni, 1952; Peard, 1996), thus also broadening the horizons for the study of veterinary diseases in Brazil.

In 1885, Lutz began publishing the results of the research he was conducting with his characteristic meticulousness. He published a vast study on ancylostomiasis, or hookworm disease – entitled "Ueber Ankylostoma duodenale und Ankylostomiasis" – in a series of articles included in Volkman's lessons in clinical medicine, published in Leipzig. These articles were later published in Portuguese in O Brazil-Medico (1888), in Gazeta Médica da Bahia (1887-1889), as well as in book form (1888). Lutz examined the hookworm and the disease it caused, from its historical, geographical, morphological, biological, clinical, therapeutic and prophylactic aspects (Deane, 1955). There were controversies as to the role of hookworms in the pathology. Many still classified them as tropical hyphemia (Edler, 1999, 1996) and considered hookworms as a consequence of disease produced by climactic factors associated with bad food, sleeping out of doors, physical depression, and other factors. According to Deane (1955, p.75-6), Lutz confirmed the observations of Grassi, Leuckhart and others regarding the free life cycle of this parasitic worm, and studied the conditions that favored its evolution, from the egg phase, eliminated in the feces of the host, to the encysted larval phase, and identified the hematophagistic nature of the adult worm, a still controversial point among parasitologists.

During the same period (1885-1886), Lutz began publishing studies on the cycle of the Rhabdonema strongyloides. The description (1885) of this species of nematode found in domestic pigs is considered one of the founding works in veterinary medicine in

Brazil.2 In addition, strongyloidiasis, the pathology it caused in human communities that ate pork meat, had not yet been studied in Brazil.

The articles that Adolpho Lutz published in the prestigious Centralblatt für Bakterologie, Parasitenkunde und Infektionskrankheiten between 1885 and 1888 regarding infestations by this and other intestinal nematodes in humans – ancylostomiasis, oxyuriasis, ascaridiasis and trichocephaliasis – proved that he knew about the work being carried out during that period by Leuckart, Grassi and other parasitologists. It was also clear that he had broad

personal experience with the problems he wrote about.3

Front cover of Klinischer Vortrage, periodical published by Richard

von Volkmann (1832-1892). BR. MN. Fundo Adolpho Lutz.

Periódicos.

Limeira, Campinas and outskirts, the region where Adolpho Lutz

practiced and first worked in dermatology, veterinary medicine and

parasitology. Carta geral do Estado de São Paulo, organized by

Comissão Geográfica e Geológica. Head engineer: João Pedro

Cardoso. Scale of 1:000000. São Paulo: Weiszflog irmãos, 1908.

At the same time, Adolpho Lutz was interacting with another emerging area of European experimental medicine – dermatology – thus guaranteeing for himself the possibility of becoming a pioneer in Brazil in this area as well. He had entered the terrain of skin diseases and, as a consequence, of pathogenic fungi and bacteria, especially through leprosy, which he studied during his entire life. He died convinced that it was transmitted by mosquitoes, a fact that indicates one more course of his prolific scientific career, entomology, discussed in another book of this collection.

In 1886, Lutz published his first paper on this disorder in Monatshefte für Praktische Dermatologie, one of the most important forums in clinical and laboratory dermatology, with the Germans in the vanguard. Lutz became involved in dermatology at the exact moment when it was being established as one of the first autonomous medical specialties in important German-speaking cities, as well as in France and England, where specialists disputed with Germans the hegemony in this area of clinical and experimental medicine.

 

Dermatology, historical milestones

"Dermology" and "dermatology" were terms coined during the second half of the eighteenth century to designate the constitution of the skin and other body membranes as objects of investigation by physicians dedicated to anatomy and pathology. In 1792, Henry Seguin Jackson first used the expressions "dermato-pathology" and "cachexiaelogia dermatica et epidermatica" to refer to a branch of medicine "that has long and often been considered important only to surgery". He set out to improve this field based on "arterio-muscular" pathology and in line with one of the nosologies available, namely, that of François Boissier de la Croix de Sauvages (1706-1767), a botanist and physician who corresponded with Linnaeus and taught at Montpellier (Holubar, 1998; Carneiro, 2002, p.37).

There were other classifications of diseases, proposed by 'systematists' of medicine, based on external symptomatic and/or morphological criteria. Among them, there was that devised by Jean Riolan in the 17th century, those of the Parisian physician Antoine Charles Lorry (1726-1783) and of the Viennese Joseph Plenk (1732-1778), and that of Robert Willan (1757-1812), of London, who some authors consider the "founder of dermatology" (Carneiro, 2002, p.37).

 

Carl von Linnaeus, Swedish physician and botanist, creator of the binomial nomenclature system for animal and plant species and one

of the first systematizer of natural sciences. Painting by Berttonier,

collection of Natural History Museum Library in Paris. Grande

Enciclopédia Delta Larousse, 1971, p.4030.

The medical treatises published in the late 18th and early 19th centuries described an increasing number of anatomic and physiological aspects of organs and tissues. The skin, for example, was no longer considered a mere envelope for the body, and took on the characteristics of a part of the body in its own, subject to lesions that could be related to certain pathological processes.

Marie-François-Xavier Bichat (1771-1802), for example, one of the leading protagonists in the birth of clinical medicine, dealt extensively with the anatomy of the dermis and epidermis. He described the influence that cold, heat and other external agents had on them, for example, and distinguished diseases that were able to penetrate the intact epidermis (such as the plague) from those that could only enter the body through lesions, such as rabies. But Bichat and other physicians who studied the anatomy of the skin and its reactions to various stimuli, considered that most pathological signs visible on the skin were mere manifestations of deeper, internal organic processes. The few skin diseases attributed to local external agents did not constitute a separate area of medicine.

The texts on the transformation of skin treatment into a medical specialty make numerous references to scientists who, since ancient times, had described visible skin diseases with greater or lesser precision. In the early 19th century, correlations between clinical conditions described – almost always based only on observation to the naked eye – and general or specific pathological processes became better established.

During this period, Paris became the hegemonic center of clinical medicine in general and in the treatment of skin diseases in particular. Nevertheless, the institutional and cognitive dynamics of one and the other became inextricably enmeshed. Most knowledge regarding dermatological diseases was generated at St. Louis Hospital, where the clinical work of Jean-Louis Alibert (1768-1837) focused on this type of disorder. In his classes he presented the family tree of the maladies of the skin, "one of the many self-reliant and complacent concepts that characterized dogmatic medicine in the early 19th century" (Calder, 1976, p.35, quoted by Carneiro, 2002, p.36).

The establishment of relationships between skin pathology and the organism in general, and the increasing efforts to draw the borderlines between dermatoses resulting from foreign causes and those of internal etiology, advanced through the writings of the clinical contemporaries of Antoine-Pierre- Ernest Bazin (1807-1878). This fact led the so-called "French school" to its pinnacle of prestige, but Bazin lived long enough to see it be surpassed by other medical centers in Central Europe, where dermatology became more rapidly known as a specialty.

The leadership in this and other domains of medicine was assumed by Germanic cities involved in the political unification that was to give rise to Germany in 1870 or in regions that were being pulled into the orbit of the new state. This difference was largely due to a system of higher education that favored the association of medicine with natural sciences, including the application to medicine of research methods developed in the context of the latter.

In the mid-19th century, cell pathology opened up new horizons for life sciences. This period also saw the development of precision methods for laboratory-based studies of observable phenomena and structures at the level of microscopic observation. The recently-acquired knowledge of the anatomy of the skin was then articulated with histopathological studies, that is, studies of lesions in tissues on a microscopic level. Especially important was the development of staining techniques that allowed samples of tissues to be observed under the microscope. Associated with the use of the microtome and improvements in optics and microscopy, these techniques increased the ability of scientists to view and precisely describe the components of objects on this minute scale. This not only broadened the frontiers of histopathology, but also created the need to re-examine and sometimes radically change the knowledge produced until then by clinicians, anatomists and physiologists. These synergies favored the development of investigations related to the micro-parasitology of skin diseases, and preceded the discoveries of Pasteur and Koch, undergoing an enormous impetus during the period when microbe hunters began exploring this and other domains of the etiology of human and animal diseases.

According to Pusey (1933, p.108-9), the essential aspects of skin anatomy and pathology had been elucidated by approximately 1900, thanks to histopathology and bacteriology, which were the underpinnings of dermatology in the late 19th century. During this period the knowledge of dermatological diseases had become so extensive and technical that it became necessary to establish a specialized branch of medicine.

 

The school of Vienna and other Germanic

dermatological centers

In 1844, Julius Rosenbaum (1807-1874) published a well-documented analysis of the studies published until then on the physiopathology of skin, concluding that the Plenck-Willan system of morphological diagnosis was inadequate for explaining dermatological diseases. Rosenbaum was the first to refer to "Dermatopathologen" agents which, through microscopic studies, were able to carry out the program proposed earlier, in 1839, by the Frenchman Gilbert Breschet (1794-1845): "si l'on pouvait, prenant pour guide l'anatomie, indiquer le siège de chaque maladie cutanée, ce serait un veritable progrès pour la médecine et pour l'anatomie pathologique" (quoted in Holubar, 1998).

At Charité, the largest hospital complex in Berlin until the Second World War (when it was destroyed), Gustav Simon (1810-1857) and Felix von Bärensprung (1822-1864) sought to chart the constitution of the skin affected by various diseases, with the aid of the crude anatomopathological instruments available. Working with sections that had been hand-cut with a knife and without adequate staining or fixation techniques, they described hypertrophies, neoplasms and vesicles of the dermis and epidermis, as well as parasites that inhabited them.

Between 1850 and 1860, Voigt, Langar, Tomsa and others described the topographic structure of the skin with great precision (Pusey, 1933, p.108). During that same period, Rudolf Virchow, a militant of social-democratic causes and of German social medicine and the founder of cell pathology, published numerous papers in Berlin related to dermatology. Besides generic texts on the history and geography of leprosy (1860, 1881) and on disinfectant soaps (1869), he published specific articles on the pathological anatomy of hair follicles, chronic pemphigus (1855), normal and pathological anatomy of nails (1857), glanders (1857); Onychomycosis (1860), leprosy (1860), warts (1863), molluscum contagiosum (1865), cells of pruritus in the epithelium (1865), tuberculosis of the skin (1865), xanthoma multiplex (1871) (ibid., p.108).

In addition, since the 1840s, the generation of Carl Rokitansky (1804-1878), Carl Wedl (1815-1891) and Ferdinand Hebra (1816-1880) had been transforming Vienna, the capital of the Austrian-Hungarian Empire, not only into the leading center of dermatology as a clinical specialty, but also a center of medical education as famous as Paris had been until 1850. During the last quarter of the 19th century, the students of these clinicians and pathologists would make up the elite of Viennese dermatopathology, including Isidor Neumann (1832-1906), Salomon Stricker (1834-1898), Heinrich Auspitz (1834-1885), Moriz Kaposi (1837-1902) and Salomon Ehrmann (1854-1926).

The most eminent of these scholars was Hebra, whose career ran parallel to the history of the Viennese institution known as Allgemeines Krankenhaus, the Germanic equivalent of St. Louis Hospital.

Rudolf Virchow (1821-1902) teaching in Berlin. Ullstein Bilderdienst

Collection, Berlin. Johann & Junker (1970, p.53, ill. 66).

 

Ferdinand Ritter von Hebra (1816-1880). Available on

www.aeiou.at/aeiou.encyclop.h/h330927

Vienna in the end on the 19th century. Grande Enciclopédia Delta

Larousse (1971, p.7018).

After graduating from medical school in 1841, Hebra became an assistant of Skoda, one of the great names in clinical medicine in Vienna and responsible for the ward specialized in diseases of the chest at Allgemeines Krankenhaus. For some reason, skin diseases had been assigned to that area of the hospital.

Like Bazin, Hebra first studied prurigo through an almost fortuitous circumstance. No one wanted to seriously study such a trivial problem, although at the time it constituted the majority of dermatological cases. Based on the notions of humoral pathology then in vogue, he supposed, at first, that prurigo was a systemic disorder, but soon noted that it was caused by a mite. In 1844, he published an article that became a classic on the subject (Über die Krätze). Experiments with other irritating substances, such as croton oil, which, when rubbed on normal skin, caused eczema, led Hebra to the conclusion that any inflammatory symptom could be induced by outside irritants, and that there were pathological changes specific to skin that could not be explained in the light of general pathology. Without denying the existence of systemic diseases, associated with the constitutional dyscrasia emphasized by the French school, Hebra began attributing greater importance to local factors in the occurrence of dermatopathologies. This emphasis soon facilitated the understanding of the role of microorganisms in the etiology of these diseases.

A student of Carl Rokitansky (1804-1878) and his successor as president of the Wiener Akademie der Wissenschften, Hebra learned to apply the most refined instruments of pathology to his specialty and, in 1845, proposed a new classification of skin diseases with twelve main categories: hyperemias, anemias, secretory anomalies of skin glands, exudations, hemorrhages, hypertrophies, atrophies, neoplasms, pseudoplasms, ulcers, neurosis and parasitosis (Costa, 1945; Carneiro, 2002, p.38).

Although he was a competent anatomopathologist, Hebra built up his reputation mainly on his clinical practice, even reacting coldly to the new conceptions of bacteriology (Pusey, 1933, 103). He showed the growth of tinea fungi on epidermis; he was the first to describe rhinoscleroma (1872), herpetiform impetigo (1872), lichen acuminatus, lichen scrofulosus and the pruritus that bears his name (Hebra's pruritus). He classified into a single syndrome – polymorphous, or multiform erythema – the numerous toxic erythemas that had until then been confusedly described. He improved the characterization of eczema marginatum, first described by von Bärensprung in 1860, and clarified the symptoms of xanthomas and pemphigus, as well as the nature of hives and pruritus as internal diseases. "As Gaucher said of Bazin, there are very few skin diseases that have not become better understood thanks to the excellent descriptions produced by Hebra" (Pusey, 1933, p.105).

Ferdinand Hebra died on 5 August, 1880, at the age of 64. Patients from all parts of the world had come to him, and the course he gave at the Vienna Medical School was the most popular among students (Pusey, 1933, p.106). The leaders of the next generation of German dermatologists, as well as many from other countries, had been trained at his clinic.

Hebra's two most important works were his monumental Atlas der Hautkrankheiten, with beautiful illustrations by Anton Elfinger (Vienna, C. Gerold's Sohn, 1856-1876), and Lehrbuch der Hautkrankheiten (Stuttgart, Enke, 1874-1876), completed by the Hungarian Moritz Kaposi (1837-1902), his son-in-law and successor

to the professorship of dermatology in Vienna.4

Kaposi also dedicated himself to clinical dermatology, describing xeroderma pigmentosum, the multiple pigmented and idiopathic sarcoma (Kaposi's sarcoma); herpes-zoster gangrenosus hystericus, dermatitis papillaris capillitii, and rhinoscleroma, studied earlier by Hebra. His book Pathologie und Therapie der Hautkrankheiten in Vorlesungen für praktische Ärzte und Studirende (Vienna, Urban & Schwarzenberg, 1880-1899), translated into French by Ernest

Besnier and Adrien Doyen, and into English by James C. Johnston, 5 was, for many years, one of the leading reference books for those beginning their studies in dermatology. In addition, his Atlas das doenças da pele [Atlas of skin diseases] (3v., 1898, 1899, 1900) is considered one of most extensive and valuable collections of illustrations in dermatology.

Another brilliant successor of Hebra was Heinrich Auspitz (1835-1886), also a professor of dermatology in Vienna. He proposed a new set of classifications for skin diseases in System der Hautkrankheiten (Vienna, Wilhelm Braumuller, 1881) and, among other contributions, published "General pathology and therapeutics of the skin," in the Handbook of diseases of the skin (New York, W.

Wood and Company, 1885), organized by Hugo von Ziemssen.6 Acanthoma and Parakeratosis are pathological alterations described and named by Auspitz, who called attention to their characteristic sign of psoriasis, the sores that bleed after scales are removed (sign of Auspitz). He also studied the vesicles and blisters of pemphigus and the effects of skin venous congestion. He was also one of those physicians that were most responsible for the widespread use of soaps in treating dermatological diseases (Pusey, 1933, p.110).

Isidor Neumann (1832-1906), the author of another important treatise on skin diseases, became especially well known as a specialist in syphilis, having set up the professorship in dermatology

and syphilis in Vienna. 7

Filip Joseph Pick (1834-1910), another of Hebra's disciples, made Prague an important dermatological center. He experimentally proved the identity between favus in humans and in rats and proved the contagiousness of molluscum contagiosum. He was the first teacher of dermatology in Austria to receive the title of professor and, together with Auspitz, founded the Archiv für Dermatologie und Syphilis in 1869, and was its editor for many years.

"Fambroesia Brasileira ou Boubas", article by Achille Breda

published in Archiv für Dermatologie und Syphilis, 1895.

In the final decades of the 19th century, under the guidance of Hebra's renowned successors and their assistants, Vienna became a Mecca for physicians of many nationalities aspiring to be recognized as specialists in dermatology. In his study, Pusey charts the dermatological centers that flourished in various important cities in Germany and Central Europe during the late 19th century due to the work of these dermatologists. Here we will discuss in greater depth one of the graduates of the School of Vienna whom Holubar (1998) identifies as the "father of German dermatopathology", and whom Herzberg and Korting (1987, p.128) consider one of the "great international founders of modern dermatology".

 

Paul Gerson Unna

Born in Hamburg on 8 September, 1850, Paul Gerson Unna was the son of Moritz Adolph Unna, a renowned physician in that busy port city. Paul Unna was also a descendent of an important family of physicians on his mother's side: she was born Ida Gerson, the only daughter of a famous surgeon.

As a continuation of this tradition, Paul began his studies in Heidelberg in early 1870, but was forced to interrupt his course when the Franco-Prussian war broke out in August. He volunteered to fight in the war and was seriously wounded near Le Mans. After the war ended in 1871, he returned to Heidelberg, then attended the university of Leipzig and finally completed his medical education in Strasbourg in 1875. His doctoral thesis, "Über die Entwicklung der

Haul" [On the Development of the Skin], 8 disclosed new facts of great importance regarding the various components of skin, which Unna had been able to observe with the use of osmic acid and picrocarmine, another staining substance recently developed by Ranvier. Unna showed that the epidermis was comprised of different strata, each consisting of further layers, with cells continuously migrating from one level to another. They are: a) the outer layer, called stratum corneum epidermidis, comprised of keratinized cells; b) stratum lucidum epidermidis, where keratinization continues; c) stratum granulosum epidermidis, where the process of cornification begins; d) stratum spinosum epidermidis, whose cell strata synthesize keratin and; e) stratum basale, the deepest layer of cells in epidermis. Unna demonstrated that stratum basale is responsible for regenerating epidermis and that stratum spinosum did not participate in this process.

 

Dermatologist Paul Gerson Unna (1850-1929). Olpp (1932, S401).

These discoveries were soon confirmed by respected anatomists and histologists, and brought fame to this young doctor. At von Ziemssen's request, Unna published the most significant conclusions of his thesis in 1883, in the chapter entitled "Entwicklungsgeschichte und Anatomie der Haut" [Development and Anatomy of the Skin], in Handbuch der speziellen Pathologie und Teraphie, referred to

above.9

At the age of 27, Unna went to Vienna to attend classes and clinical demonstrations given by Ferdinand Hebra, by his son Hans Hebra, by Moritz Kaposi and Heinrich Auspitz. He was also pleased to accept an invitation from Auspitz to participate in microscopic studies intended to clarify the pathological anatomy of syphilitic chancre. In 1877, Auspitz and Unna published two articles on this topic in Vierteljahresschrift für Dermatologie & Syphilis.

In October, 1876, Unna took on the position of assistant physician in the syphilis ward of St. Georg Hospital, in Engel-Reimers. Later, he joined his father's clinical team in Hamburg, taking care of nighttime visits and visits to homes of patients living in remote places.

As the number of his dermatological patients grew, Unna decided to

start his own specialized clinic in skin diseases. 10 Joining forces with Oskar Lassar and Hans Hebra in 1882, he founded a journal entitled Monatshefte für praktische Dermatologie, the first periodical dedicated to dermatology in Germany and, for many years, one of the leading catalysts in this specialty, which was beginning to

develop in other countries, including Brazil, as we shall soon see. 11

Unna had only two assistants at his clinic and soon became unable to keep up with the growing demand. Therefore, he decided to abandon his work as general practitioner and concentrate exclusively on dermatology, an unprecedented move in Germany at that time. In April 1884, he opened the modern facilities of the new dermatological institute in an outlying district of Hamburg called Eimsbütte. It consisted of three pavilions for patients, one for physicians, with well-equipped laboratories, and his own residence.

At that time, there was no organized or obligatory training for those preparing for medical specialties. As a result, Unna's Dermatologicum began attracting ever-greater numbers of students

from Germany and other countries. In 1886, 12 its scope was widened and he began offering graduate courses in anatomy, histopathology, bacteriology, mycology, pharmacology, chemistry and photography. All these courses were associated with the intense clinical practice carried out with the patients who came to his clinic in large numbers.

Front cover of periodical Monatshefte für Praktische Dermatologie, in

1910, when it was published by Paul Gerson Unna and Paul

Taenzer. Special edition with an article by Unna and Golodetz on

skin chemistry.

Partial view of Dermatologicum façade (1884). This famous clinic

was founded by Unna in Hamburg. Crissey, Parish, Holubar (2002,

p.67).

Some of the first physicians trained there became recognized pioneers of dermatology in various countries: Pollizer, from New York; Török, from Budapest; Tommasoli and Mibelli, from Italy; Eddowes, from London; Noys, from Melbourne; and Sir Norman Walker, the English translator of Die Histopathologie der Hautkrankheiten (Berlin, A. Hirschwald, 1894), written by Unna and considered a milestone in the history of dermatology. There were also Buzzi, Santi, Ernst von Düring, Hodara, Engman and, last but not least, the Brazilian Adolpho Lutz.

 

Adolpho Lutz in Hamburg

According to Olpp (1932), Unna and Lutz first met at the 58th Meeting of German Naturalists and Physicians held in Strasbourg in 1885, where Lutz presented a short communication about a disorder he had observed in a sizeable number of children in and around Limeira, Brazil. It was a strange disease that began as a catarrhal affliction and evolved into a "peculiar" dermatitis. In its more serious forms, the stains on the skin formed large, dark violet confluent strips and fell off in large scales. The course of the disease was slow and could lead to death. Since Lutz observed it only in small children that had already been weaned or that consumed other food products besides their mother's milk, he suspected that the cause might be related to cornmeal, a food consumed by many of the children.

This etiology also corresponded to the fact that the illness had a

certain similarity to pellagra, that was already known to be

related to the consumption of spoiled corn. The disease was

even more similar to Erythema epidermicum or with acrodynia,

whose etiology is still unknown. However, this latter disease

cannot be identified with that we see today because their

descriptions differ in essential points.

In fact, the contact between Unna and Lutz was prior to the 1885 congress. Lutz, always attentive to advances in European experimental medicine, probably subscribed to Monastsheffe für Praktische Dermatologie, in which the communication he presented in Strasbourg was published (Lutz, 1886a).

Lutz had already published important articles in Germany, of which Unna was undoubtedly aware. His study on Rhabdonema in pigs and on the diagnosis of Rhabdonema strongyloides in human beings was published in Centralblatt für Klinische Medicin, in June, 1885 (Lutz, 1885a). In the same year, Deutsche Zeitschrift für Thiermedizin published his observations on intestinal parasites in pigs and other domestic animals and regarding the occurrence of the same species in humans (Lutz, 1885-1886). Also in 1855(b), a long paper on the Ankylostoma duodenale and ancylostomiasis was included in the well-known Sammlung Klinischer Vorträge [Lessons in Clinical Medicine], published by Richard von Volkmann, in Leipzig.

All indications are that it was leprosy that brought Adolpho Lutz and Paul Gerson Unna together. One of the buildings at the Dermatologicum, opened in 1884, was reserved for victims of leprosy, most of whom came from South America (Hollander, 1987, p.85). It was also at this time that Unna began to study the bacteriology, pathology and treatment of the disease. In that same year he took part in a medical congress in Copenhagen where the topic was under discussion. He then visited Norwegian Leprosaria and established a productive relationship with Gerhard Armauer Hansen (1841-1912), the discoverer of Bacillus leprae, and with Daniel Cornelius Danielssen (1815-1894) and Carl W. Boeck, who, in 1848, had established the distinctive characteristics of this

disease on the basis of scientific observation.13

 

Hohe Brücke (High Bridge) seen from Kehrwieder, in Hamburg,

Germany. Photo by G. Koppmann & Co., September 1884.

According to Olpp (1932), in 1885 Unna treated a German patient who had acquired leprosy on a trip to Brazil – he may have been referred by Lutz – and obtained satisfactory results with pirogalol. This case gave him data for his paper on the histology and treatment of the disease, which he later presented at the Congress of Internal

Medicine in Wiesbaden.14

In March, 1885, Adolpho Lutz left Limeira for a period of study at Unna's clinic. Under his guidance, Lutz became interested in the bacteriology of leprosy, and also studied the structure and biology of germs related to other diseases, including tuberculosis, whose bacillus showed intriguing analogies with those described by Hansen

regarding leprosy. 15 Shortly thereafter, Lutz published a paper on Hansen's bacillus in Monatshefte für Praktische Dermatologie (1886b), which considerably changed the concepts then in vogue concerning not only this microorganism, but also those regarding the bacteria discovered by Koch. Lutz showed that these two organisms had common characteristics that were different from those of other bacilli, and proposed that the two be classified as species of a new genus.

 

Lutz and controversies over the causal agent of

leprosy

Leprosy was one of the first infectious diseases to be re-structured in the light of microbiology. In 1848 Danielssen noted that certain cells found in leprous tissues were characteristic of leprosy. Hansen observed small rod- shaped corpuscles in the cells of skin tubercles. These corpuscles were large round mononuclear cells, that Virchow called "leprous cells". Because of their constant presence in leprous lesions, Hansen suspected that they were the cause of the disease and called them Bacillus leprae. In 1874, Hansen described his observations to the Medical Society of Christiania, and his position was soon confirmed by Theodor Albrecht Edwin Klebs (1834-1913) (Bulloch, 1938, p.9, 376).

Albert Neisser (1855-1916) produced a more consistent description of the bacillus in an article published in 1879, thanks to staining processes, which were becoming increasingly important in the observation of microorganisms in general. When Niesser's article was published, Hansen quickly reacted to guarantee the priority of his work, and published his own theory in German, English and Norwegian. Hansen's bacillus thus "became one of the first to be classified as a specific pathogenic microorganism in human beings,

a great advance for the incipient science of bacteriology". 16

At the same time that Adolpho Lutz was beginning his investigations, an intense controversy was raging among bacteriologists as to exactly where the leprosy microbe lodges in human tissues and liquids. This controversy was associated with another problematic question, the difficulty of cultivating the microorganism in vitro and replicating it in the tissues of other animals. The interpretation of what the various specialists saw depended largely on what staining and fixing techniques they used to prepare the tissue samples they intended to put under their microscopes, and innovations were constantly being made in these techniques.

Staining methods had been used in histology before they migrated to the study of bacteria. The objective of these methods was to fix staining substances in certain components of tissues or organisms, so that their forms and structures could be seen more clearly. Goeppert and Cohn (1849) were the first to work with preparations of fuchsin dye, later improved by Hartig (1854) and Gerlach (1858). The Bohemian physiologist Jan Evangelista Purkinje (1787-1869) introduced the use of balsam fir, of glacial acetic acid and of potassium bicromate. He was the first to slice tissues in order to study them under the microscope. Logwood extract or

(Haematoxylum campechianum)17 was used by Waldeyer (1863). Böhmer (1865) improved the technique by adding alum to the substance. The aniline or coal tar stains began being used in 1856 and were eventually used in household and industrial processes for dyeing cloth. Hermann Hoffmann (1819-1891), a botany teacher in Giessen, was the first to stain bacteria. A short time later, Weigert (1871) showed that carmine served to stain cocci. In 1875, he discovered that alkyl also gave surprising results in staining tissues and bacteria. In 1877, C. J. Salomonsen (1847-1924) succeeded in staining tissues and bacteria in an aqueous solution of fuchsin dye.

Albert Neisser (1855-1916). (Olpp, G. 1932, S290).

 

Koch (1877) improved staining methods even further and classified them according to the acidic, basic or neutral PH levels of the substances used. To immobilize the bacteria he developed an ingenious process of drying that did not affect their natural form. His method for fixing bacteria included the use of alcohol to interrupt the organisms' metabolic activities. Microscopic cuts and preparations were soaked in various types of stains, such as methyl violet 5 B, fuchsin dye, brown aniline and, especially, gentian violet. Samples were placed in an aqueous solution of potassium acetate or balsam fir. These procedures enabled Koch to discover, in 1882, the bacillus that bears his name, the agent of tuberculosis.

In subsequent years, other staining methods also became widely used in laboratories and were frequently mentioned in the increasing literature on the topic, which referred to specific methods for staining spores, cilia and capsules of microorganisms. Some formulas made their way into the treatises that began to establish bacteriology as a "normal" science, in the sense used by Thomas Kuhn (1970). In the excellent pages that Bulloch dedicates to the subject (1938, p.213-30), he also makes reference to Ehrlich's improved staining of the tuberculosis bacillus in 1882 and describes Loeffler's use of alkali and methlyene blue in 1884, as well as the use of carbolic acid (phenol) instead of aniline by F. Ziehl (1857-1926), and the use of sulfuric acid instead of nitric acid by F. Neelsen (1854-1894). The Danish scientist Christian Gram (1884), working in Berlin, developed the method universally known today, which consists of the use of ammoniacal fuchsin dye and of the division of bacteria into gram positive and gram negative, depending on whether they fix stains or not.

A look at some of the medical publications of the time will give the reader a vague idea of the importance of the events that led us to this digression on the conflicting notions regarding the leprosy bacillus and the different techniques used to study it. Adolpho Lutz's article stirred up a number of reactions, especially in the recently founded annual journal published by Dr. Paul Clemens von Baumgarten (1848-1928), professor of pathological anatomy in

Königsberg, 18 entitled Jahresbericht über die Fortschritte in der Lehre von den pathogen Mikroorganismen (1885-1911).

Neisser had held that the leprosy cells described by Virchow in pre-bacterial times were specific to the disease because they were full of bacilli. In 1885, Unna expressed the opinion that these objects were not cells at all, but conglomerates of free bacilli embedded in mucin and surrounded by cells of atrophied connective tissue. The leprosy bacillus was not to be found in the cells of the tissues, asserted Unna in 1885-1886, but rather in the lymph system. His observations had also shown that clumps of bacilli were uniformly distributed and circulated freely through the tunica intima of arteries and veins. This led observers to believe that the patients' bodies – especially those who suffered from the nodular form – contained millions of bacilli.

Unna's controversial observations were related to a new method of staining he had developed to overcome a failure he noted in the methods employed until then to study leprosy. According to him, stains and balsams failed to show long-lasting results, and the substances present in the decolorizing and fixing agents affected the results, because of their "oxygenophilia," that is, their tendency to steal oxygen. To solve this problem, he developed the "dry method," by which the sample, after going through the customary stages of staining, discoloring by acid and, sometimes, a second staining, was taken directly from the water and carefully placed on the glass slide. The excess water was removed with tissue paper and the slide was carefully placed over the flame of the burner until dry. A drop of the balsam chosen as fixing agent was then added to the totally dry section, while the slide was still hot. Besides being more practical and cheaper, this technique showed the relationships of the

microorganism with the surrounding tissues more clearly. 19

To judge from the reviews published in the volumes edited by Baumgarten in 1886-1889, Unna faced serious criticisms from several eminent specialists in the matter. Hansen stated that "dry preparation" changed the morphology of the cells, making those of leprosy disappear and leaving only tissue cells. He also argued that, if the bacilli circulated freely through the lymphatic vessels, they would penetrate into the blood and cause acute pathogenic states, whereas the disease always had a chronic nature. The bacilli must

therefore be "imprisoned" inside the cells.20

 

Sketch of Mycobacterium leprae (Arm. Hansen) Lehmann et

Neumann. (bacillus leprae). I. Microscopy preparation of nasal

mucus. II. Histologic cut: lymphatic ganglion; slightly larger; bacilli are not in giant cells, as in tuberculosis, but in clumps. III. Histologic cut: lymphatic ganglion; slightly larger. Lehmann & Neumann (1910,

plate 68).

Sketch of Mycobacterium tuberculosis (Koch) Lehmann et Neumann

(Tuberculosis bacillus). V. Cultivation of potatoes. VI. Microscopy

sputum preparation, coloring by Ziehl. VII. Microscopy sputum

preparation: "typus humanus" plasmolithic forms. VIII. Microscopy

preparation of pus from a cow's uterus tuberculosis. IX. Clumps of

differently-shaped decomposed tuberculosis bacilli; preparation of

human sputum. X. Microscopy preparation of human sputum:

colonies of tuberculosis bacilli. XI. Histologic cut: human lymphatic

ganglion; giant cells can be seen in the necrotic tissue. XII.

Histologic cut: lymphatic ganglion; two giant cells surrounded by

necrotic tissue. Lehmann & Neumann (1910, plate 67).

Neisser held that Unna's dry method could contribute to the study of cell morphology, but it was inappropriate for investigating the location

(topography) of the bacilli.21

Another critic, Karl Touton (1858-1934), peremptorily stated that "Most leprosy bacilli are found in the leprotic tissues, as has been generally accepted until now, and closed inside the cells in larger or smaller clumps. These agglomerates of bacilli, therefore, are not cells, but parts or inhabitants of cells. In general, 'free' clumps come from inside cells."

Touton attributed Unna's error to his method, holding that the steam from the water used during the process made the cell membranes "explode," thus giving the impression that the bacilli were free in the lymph. In addition, drying by fire reduced the thickness but not the area of the tissue samples. Their various superimposed layers were thus reduced to a single surface, making it more difficult to examine the material. There was no doubt that Unna's method changed the natural order of things and gave origin to "artifacts" with unreliable

results.22

Two other critics of Unna were Beaven Rake and Sudakewitsch. The former saw bacilli so near the nucleus of the cells extracted from a nodule of leprosy that their location, for him, was undeniable. Sudakewitsch, of the Institute von Münch, in Kiev, studied cases of "secondary nervous form" (that is, cases where the skin showed only remains of extinct leprous infiltrates) in order to understand the relationship between the bacillus and the nervous system, and the changes undergone by the ganglia in the course of the disease. Sudakewitsch proved that there were bacilli inside ganglion cells. They were sometimes found inside the controversial vacuoles that the author called "parasitic" vacuoles because he held that they were the result of "intracellular digestion" processes. From his point of view, both degenerated bacilli and destroyed nervous cells were due

to the battle between bacilli and cells.23

Besides the extra-cellular location of Hansen's bacillus, which was

also contested by Bidenkap and Campana but upheld by Kuhne,24 other aspects of the etiological agent of leprosy were debated. Unna was able to observe the vacuoles first described by Virchow, but in Neisser's opinion they were only artificial results of Unna's dry method. According to Unna, some of these vitreous masses observed in preparations were areas filled with bacillary mucous, while the remainder consisted of the lumen of the lymphatic vessels, free of bacilli. For Touton they were the product of the hydropic degeneration of the cells' protoplasm. In his opinion, bacilli that came into contact with a lesion on an individual's skin arrived at the cells through the lymphatic vessels and developed large colonies in the protoplasm. The vacuoles were indicators of the degeneration of protoplasm caused by the growth of the parasite. Vacuoles gradually grew and multiplied, cells swelled until they burst, and bacilli, now free, invaded lymphatic crevices, blood vessels, sudoriferous glands and other tissues and cavities (Doyon, 1887, p.429-30).

Another controversial point was in relation to the spores that some bacteriologists noticed inside the bacilli. Discontinuous staining and granular formations had already been observed in these rods, including those of tuberculosis. For some time, Koch had supposed they were spores, and Neisser came to a similar conclusion regarding the leprosy bacillus.

In an article published in 1886, Lutz (1886b) provided detailed evidence to support Unna's thesis and went even further. He held that the masses which Touton considered clumps of bacilli lodged inside the cells of leprosy not only were not there, but also did not

consist of bacilli.25

Thanks to a new method of staining he developed with Unna, Lutz saw and described objects that to other observers had seemed anomalies, or sporadic accidents.

According to Lutz, the microbes of leprosy were found in the lymph, in pus and in cuts of the diseased organs, alone or grouped in gelatinous envelopes or mucous. Even the isolated bacilli often showed the enveloping substance that, in Lutz's opinion, played a major role in the formation of leprous neoplasias. The forms that did not have this wrapping consisted of an "early stage" of the microorganism.

When the envelope grew beyond a certain volume, the tenuous outlines of the rods were no longer visible and the observer had to use other methods to discern the nature of those conglomerates. The envelopes seemed to be very similar to the gelatinous masses often found among algae and fungi, and staining by gentian violet showed that their composition was analogous to that of the pneumonia cocci described by Friedländer. Unna held that these masses were not cells, nor were they located inside cells.

Lutz then described in detail the techniques that had allowed him to understand the nature of the clear spaces that interrupted the continuity of the rods, making them, as was said, non-homogeneous. For Neisser, they were places where interstitial spores were formed. Employing Gram's method and discoloring by acidified alcohol, Lutz obtained sharp images of micrococci arranged in regular rows and connected by fine filaments.

He therefore came to the conclusion that the constitutive part of the presumed leprosy bacillus is the small round cell similar to a coccus with a very fine membrane at the tip that gradually thickens and becomes colloidal. The cell contained in this membrane broke down into two new cells that gradually moved apart and acquired new envelopes, without failing to be included in the former ones. Interstices between the cells were larger than the cells themselves. They always became dismembered in the same direction, in linear series that formed like a string of pearl, or rods. The gelatinous envelope around them constantly grew in size as cells acquired more layers. This gelatinous agglomerate could fuse with its neighbors into a common mass.

Lutz identified a third aspect that also failed to fit into the usual descriptions: at the tip of the rods he found oval cells with double outlines that were different from the others in their volume, their bright color, and their elongated form, with one or two filiform extensions that looked like the stem of a musical note. These cells seemed to have a "special form" that seemed to play some role in

the reproduction of the microorganism. 26

If this description is correct, wrote Adrien Doyon (1886, p.427) in Annales de Dermatologie et de Syphiligraphie, the name bacillus is inappropriate. Accordingly, Lutz proposed that the leprosy bacteria be classified in a division of the genus Coccothrix, into which, without hesitation, he would "place the tuberculosis parasite".

In another article published in the periodical edited by Unna, Lutz (1886c) sought to break down the characteristics of the microorganisms that could be included in the genus he considered necessary to create, placing there not only Hansen's bacillus, but also the supposed agents of malaria and syphilis: the bacillus recently described by Matterstock, and the Bacillus malariae of Klebs and Tommasi Crudelli, respectively.

There is almost no information about the former.27 And, as we have seen, Klebs was the first to prove the existence of Hansen's bacillus. In 1883, he discovered the diphtheria bacillus, which, in the following year, was cultivated by Friedrich Löffler, a member of Koch's team, and which first became known as the Klebs-Löffler bacillus (now known as Corynebacterium diphtheriae). In 1878, Klebs, together with Tommasi Crudelli, began doing research on the malaria bacteria, which had been endemic in the Roman CampaSgna. The American J. H. Salisbury, the Italians Lanzi and Terrigi, as well as Pietro Balestra, had blamed the disease on microscopic algae that apparently lived in swamps (Busvine, 1993, p.18). Klebs and Tommasi Crudelli found Bacillus malariae in the blood of patients with fever. This agent was a microscopic plant apparently similar to anthrax bacillus, whose spores Koch had recently come across in places where animals were buried. The malaria bacillus, therefore, probably lived in the soil and floated in the air, a discovery that was

soon confirmed by several Italian and French investigators.28

Lutz's efforts (1886c) in "Ueber die Beziehungen zwischen Stäbchen und Coccen" to fit his theory to the descriptions of the supposed malaria and syphilis bacilli were related to another set of controversies involving basic aspects of the incipient science of microbes.

Heated controversies over the world of microbes

The division of living beings into two kingdoms was a basic axiom of natural history. The Swede Carl von Linnaeus, (1707-1778), published his most important work, Systema naturae, in 1735, and, in the following year, Fundamenta botanica. He gave Latin names to species of animals and plants, thus establishing the binary nomenclature still used today. Although he dealt especially with plants, he gave new classifications to animals as well.

In the late 17th century, a particular species of naturalists, the microscopists, published descriptions of living beings that were invisible to the naked eye. These scientists took great pleasure in spending long hours with one eye glued to a microscope, an instrument that had been perfected by Anton van Leeuwenhoek. With it, they observed animalcules that inhabited even the most familiar everyday objects. For a century and a half, the microbian world was "an object of enchantment and entertainment for amateur microscopists" (Stanier and Lwoff, 1973, p.1191).

To classify microorganisms, 29 an easily visible criterion was first used, mobility. Anything that moves is an animal, and what is stationary is a plant. The first attempt at organizing animalcules into a system of classification similar to that of Linnaeus was the work of the Dane Otto Friederich Muller (1730-1784). In Animalcula infusoria et marina (1786), he set up two groups that were distinguished by the possession or lack of external organs (Membraneceae and Crassiuscula). C. G. Ehrenberg (1795-1876) called animalcules Polygastrica, because he presumed they had stomachs, and in Die Infusionsthierchen als volkommence Organismen (1838), classified them into 22 families.

Under the influence of the cell theories formulated by physician René Joachim Henri Dutrochet (1824), botanist Matthias Jakob Schleiden (1838), zoologist Theodor Schwann (1839) and pathologist Rudolph Virchow (1858), microscopists began establishing categories to distinguish microorganisms comprised of numerous cells, from the unicellular Infusoria. In his book Histoire naturelle des zoophytes (1841), Felix Dujardin (1801-1860) was the first to separate the single-celled beings that showed distinct and relatively large cells (protozoa) from the vibriones, much smaller filiform animals, apparently without internal differentiation and without locomotive organs, consisting of the genera Bacterium, Vibrio and Spirillum.

The borderline between animals and plants was becoming increasingly obscure at this level of observation. The criterion of motility soon lost its meaning, since algae and mushrooms reproduced by means of spores that moved within the field of the microscope. In addition, Casimir Joseph Davaine's studies on anthrax indicated that its 'animalcule' remained absolutely motionless for part of its life cycle. It was also seen that certain protozoa contained chlorophyllous pigment, a fact that led Maximilian Perty (1852) to create the category of animal-plants, or Phytozoidia, to account for these anomalies.

First classified in the animal kingdom together with protozoa, bacteria became the object of controversy among botanists, who were unsure as to how they should be classified in the plant kingdom. Carl Wilhelm von Nägeli (1817-1891), a botanist working in Munich, joined several genera together into a group he called schizomycetes, classifying them with primitive colorless plants, the mushrooms (1857).

Based on Darwin's thinking, Ernst Heinrich Haeckel stated, in 1866, that plants and animals only made sense as evolutional lineages that led to vascular plants, on the one hand, and to the metazoa, on the other. Since the microbian world is comprised of older evolutionary lineages, it constitutes a third kingdom, the protists. Most botanists and zoologists, however, rejected this solution, and the debates as to

the classification of microorganisms raged on. 30

Carl Wilhelm von Nägeli (1817-1891). Institut für Geschichte der

Medizin Collection, Munich. Mazumdar (1995, p.25).

Bacteria were associated with a particular group of algae, the Cyanophyceae, by Ferdinand Cohn, a botanist working at the University of Breslau and author of the system that became the cornerstone for classification in all treatises on bacteriology and medicine since the late 19th century. William Bulloch attributes to him the invention of the word "microbe," used by Sedillot and sanctioned by Littré, coined to give some semblance of order to the