Camillo Golgi (1843-1926) and the “Mystery of Periodic Fevers”

The name of Camillo Golgi is usually associated to his pivotal discoveries in the field of neurosciences (the “black reaction” that paved the way to the study of nervous cells and earned him the Prize Nobel in 1906) and in the field of cell biology (in particular the discovery of the intracellular apparatus that holds his name). However, Camillo Golgi deserves our gratitude also for his pioneer investigations on malaria in the years immediately following the discovery of the etiologic agent of malaria by Alphonse Laveran in 1880 at Constantine, in Algeria. In particular, this brief note is intended to pay tribute to the contribution of Camillo Golgi to the understanding of the parasite biology and life cycle, leaving aside his other better-known discoveries.

 Immage of Camillo Golgi, at the time he was Chancellor of the University of Pavia Bartolomeo Camillo Emilio Golgi was born on July 7th, 1843, in a remote mountain village (Pisogneto di Corteno, later renamed Corteno Golgi) of Camonica valley near Brescia, in northern Italy, as the third son of the local physician Alessandro Golgi and of his cousin Carolina Golgi, both native of the famous University town of Pavia. At the age of fourteen he moved to Lovere, on the shore of the lake of Iseo, to attend secondary school before moving to his family origin town of Pavia, following his fathers’ paths, to attend the School of Medicine at the local University.

At that time, the University of Pavia (Alma Ticinensis Universitas) was at the zenith of its millenary glory and was considered among the best Universities in Europe after a number of famous writers (Ugo Foscolo, Cesare Beccaria) and scientists (Giovan Battista Morgani, Lazzaro Spallanzani, Alessandro Volta) attended the University. Although Pavia was indeed a very different place from his small mountain native village, Camillo Golgi soon proved to be a brilliant university student and graduated on August 7th, 1865, under the mentorship of the famous criminologist Cesare Lombroso, defending a memory on the pathogenesis of mental diseases.

At first fascinated by the Lombroso’ positivistic approach to psychiatry, Camillo Golgi worked with him at the psychiatric Clinic until 1869, when he felt unsatisfied by the vague pseudoscientific methods of Lombroso. During those years, Camillo Golgi was attracted by the work carried out by the young scientist Giulio Bizzozero at the Laboratory of Experimental Pathology at the Botanic Gardens in Pavia. Giulio Bizzozero, although younger than Golgi by three years, was always considered as a true mentor by Camillo Golgi for his managerial and scientific skills that enabled him to carry out pivotal studies on phagocytosis, on the hematopoietic properties of the bone marrow and on the role of platelets on thrombogenesis. The encounter with Giulio Bizzozero resulted to be very fruitful for Camillo Golgi from both the personal (he married Bizzozero’ niece Lina Aletti later in 1877) and the scientific sides. In fact, the passion of Golgi for the study of neurosciences was empowered by his increasing skills in the use of microscope, that Bizzozero mastered perfectly. Under Bizzozero’s guidance, Camillo Golgi focus its scientific work on neuro-histology, a field where he starts using chrome and silver nitrate, the basis of the future “black reaction” that will earn him the Nobel Prize later in 1906. Golgi published many scientific contributions on the fine structure or the nervous systems in the following years. However, he did not held a stable position at the University of Pavia and, despite Camillo Golgi’s reticence, his father Alessandro finally forced him to move from Pavia to work as a clinical physician in a hospice for beggars in the town of Abbiategrasso, where he stayed from 1872 to 1875. Despite the poor professional satisfaction for a brilliant scientist, Golgi managed to organize a real laboratory in his new house’s kitchen, where the formula of the “black reaction” to permanently stain the nervous cells finally was finalized even if, as it is the fate for many scientific discoveries, its importance was internationally recognized only over 15 years later. While still in Abbiategrasso, and much more when he managed to return to Pavia in 1876 as Professor of Histology, Camillo Golgi performed an impressive series of experimental works on the fine cerebral structure. Later in 1881 he was charged by the University of Pavia with the official teaching of General Pathology, while retaining that of Histology, and he was also appointed head of a small clinical unit at the S. Matteo Hospital in Pavia, pioneering the practice of “bed-side science” that will be especially fruitful in the field of malaria

It may sound strange that the name of a scientist is associated to so different fields such as infectious diseases – malaria in particular – and neurosciences. Such apparent discrepancy may be better understood if one considers that Golgi was completely absorbed by the positivistic atmosphere of his times, when microbiology was at its vigorous infancy, and that he perfectly mastered the use of the positivistic instrument per antonomasia, the microscope. Furthermore, Pavia was a privileged place for microbiologic studies as the echoes of the studies of Lazzaro Spallanzani and Agostino Bassi still permeated the scientific live of the small Italian university town.

The fascinating world of microbes attracted the attention of Camillo Golgi since the beginning of the 1880s and he dedicated himself to this new discipline with the same tireless passion that he used to study the nervous system. Also in the field of infectious diseases the microscope, in Camillo Golgis’s hands, took the connotation of a dynamic – and not static – instrument, providing mighty results. The importance of the work of Golgi in infectious diseases is not only in his personal extraordinary contributions, but also in the wide array of his brilliant disciples who also contributed to the advancement of sciences in this field, such as Adelchi Negri (the rabies “Negri” bodies), Giovan Battista Grassi (discovery of the human anophelic cycle of malaria), Antonio Carini (of Pneumocystis carinii fame), Giuseppe Sanarelli and others.

Cover of the book edited in 1929 by Prof. Aldo Perroncito , successor of Camillo Golgi at the Chair of General Pathology of the Universiity of Pavia, collecting his papers on malaria

In particular, apart from contributions about antrax and Strongyloides stercoralis, malaria particularly attracted Golgi’s interest after Laveran (1845-1922) first observed parasites in the blood of a malaria patient on November 6th, 1880. It is to be reminded that Italy was a heavily malaria endemic areas, with important health and social impact. Even after Laveran’s observation were lately confirmed by the Roma malariological school – the most scientifically sound at that time headed by Ettore Marchiafava and Angelo Celli – a number of questions still remained unsolved: (i) why different fever periodicity existed in different seasons and in different locations of Italy? (summer-autumn fevers around Rome and spring fevers near Pavia?); (ii) why malaria may have such different outcomes, ranging from fatal cerebral cases to oligo-symptomatic fevers?; (iii) which is the most appropriate timing for quinine administration?

Camillo Golgi was passionate by these unsolved questions and started working on malaria, in close contact with the Roman malariological school of Marchiafava and Celli at the Santo Spirito Hospital in Rome, where he spent a short period of time in September 1885. Back to Pavia, he started his work observing the daily blood smears from the malaria patients staying at his clinical unit at the hospital. Surely, he was favoured by the fact that in autumn in Pavia malaria was invariably of the quartana type (“febbre lunga”, i.e. long fever), thus permitting homogeneous observations. After only a few months of hard work, in November 1885, Golgi was able to report at the Royal Medical Academy in Turin the complete dynamic cycle of what we now know to be Plasmodium malariae, coupled with the clinical observation of the feverish attack, described as follows:

(1) progressive development of pigmented bodies leading to the complete disappearance of the globular substance during 2 apyretic days until 6-12 hours preceding the new attack, (2) subsequent transformation of the new pigmented bodies (...) in new entities with central concentrated pigment and peripheral segmentation appearing soon before or concomitantly with the new attack, (3) rapid disappearance of the segmented forms with the appearance of fever …...”

The mystery of periodic fever was unveiled, thanks to the unique capacity of Camillo Golgi of associating his “bed-side” clinical findings with the detailed and patient interpretation of the microscopic observation. Further to this, Golgi concluded that the feverish attacks could be predicted by a simple microscopic exam, when the segmentation process was going to mature:

“In quartan fever (….), the observation of mature and segmented forms herald the close proximity of a feverish attack, so that (….) microscopical observation makes it possible to predict the next attack …………..”

Based on these findings, Golgi also tried to correlate the timing of administration of quinine with the microscopic appearance of the parasites. The evidence that the effect of quinine was minimal when segmentation had already started is most probably the first demonstration of the schizonticidal effect of the bark of Cinchona, long before pharmacokinetic studies. Again, despite the fact that Golgi predominantly observed benign P. malariae cases as it was normally expected in Pavia in autumn, he could also quantitatively correlate the amount of circulating parasites with the severity of the disease, a finding not yet reported:

“As to the relationships between the amount of circulating organisms and the severity of the attack, in general, I found a direct correlation, since the higher the number of the organisms, the more severe the attack;....”

However, he soon realized that his observations could be applied to autumn malaria (“quartana” or “febbre lunga”, i.e. long fever), while a different type of malaria should be hypothesized to occur in Rome and even in the countryside around Pavia during spring. Despite the unique name of “malaria”, in fact, different microscopic appearance of the intracellular parasites was evident, as he wrote to E. Marchiafava in early 1886. Urged to solve this dilemma, he started to observe tertian malaria cases in Pavia in the following spring and he was able to report on June 5th, 1886, to the Medical Society of Pavia the complete human schizogonic cycle of what is now known to be Plasmodium vivax.

In only few months, the patient and detailed work of Camillo Golgi paved the way to the comprehension of the dynamic events that constitute the life cycle of two highly prevalent plasmodia in Italy, facilitating the later work of Marchiafava and Celli who described the life cycle of the parasite causing tertian malignant malaria
(P. falciparum), most prevalent in the Roman countryside, a few years later in 1892. It is to be reminded that all the work of Golgi was performed before specific Romanowsky stain was available, giving even more credit to the highly sophisticated skills of the scientists!

Camillo Golgi was awarded the Nobel Prize in 1906, ex-aequo with the Spanish scientist Santiago Ràmon y Cajal, for his works on the microscopical structure of the nervous system. However, at least two other discoveries (the Golgi apparatus in 1898 and the first description of the biological cycle of a malaria parasite in 1885) could have earned him the highest honor in the scientific academy.

Selected Literature and Further Reading

Goldaniga, G. & Marchetti, G., 1993. Vita e opera dello scienziato camuno Camillo Golgi. Tipolitografia Lineagrafica (Life and achievements of the scientist Camillo Golgi, from Val Camonica), Boario Tenne, Brescia.
Golgi, C., 1886a. Sull’infezione malarica (On malaria infection). Archivio per le Scienze Mediche, 10: 109-135.
Golgi, C., 1886b. Ancora sull’infezione malarica (Again on malaria infection). Bollettino della Società Medico-Chirurgica di Pavia, 1: 51-53.
Golgi, C., 1888. A qual punto del ciclo evolutivo dei parassiti malarici la somministrazione della chinina, arrestandone lo sviluppo, valga ad impedire il più vicino accesso febbrile (When, in the parasite life cycle, it is most appropriate to administer quinine to prevent the next feverish attack). Bollettino della Società Medico-Chirurgica di Pavia, 3: 39-42.
Golgi, C., 1890. Sulle febbri intermittenti malariche a lunghi intervalli (On intermittent long-interval malaria revers). Archivio per le Scienze Mediche, 14: 293-313.
Golgi, C., 1893. Sulle febbri malariche estivo-autunnali di Roma (On summer-autumnal malarial revers in Rome). Lettera del Prof Camillo Golgi a Guido Baccelii. Gazzetta Medica di Pavia, 2: 481-493.
Mazzarello, P., 1996. La struttura nascosta. La vita di Camillo Golgi (The hidden structure. Life of Camillo Golgi). Istituto Editoriale Universitario, Cisalpino.

Francesco Castelli
Professor of Medicine (Infectious Diseases)
University of Brescia
Brescia, Italy

Published the 20th February 2013