Laveran

Charles Louis Alphonse Laveran, a calm, reserved, unemotional French Military Surgeon, won the Nobel Prize for Medicine and Physiology in 1907 for his discovery of the malaria parasite and other significant contribution to parasitology. Laveran, a stiff, aloof, quiet man, as slow and methodical in his speech as in his work, was exceptionally astute both as physician and scientist.

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Laveran

Laveran

Laveran was born in Paris on June 18, 1845 in a family of doctors, in the house which was formerly No. 19 rue de l’Est but later became, when this district was rebuilt, a hotel, Boulevard St. Michel. His father, Dr. Louis Théodore Laveran, was an army doctor and a Professor at the École de Val-de-Grâce; his mother, née Guénard de la Tour, was the daughter and granddaughter of high-ranking army commanders. When he was very young, Alphonse went with his family to Algeria. His father returned to France as Professor at the École de Val-de-Grâce, of which he became Director with the rank of Army Medical Inspector. Alphonse, after completing his education in Paris at the Collège Saint Baube and later at the Lycée Louis-le-Grand, wished to follow his father’s profession and in 1863 he joined the Public Health School at Strasbourg. In 1866 he was appointed as a resident medical student in the Strasbourg civil hospitals. In 1867 he submitted a thesis on the regeneration of nerves. After his training, he was assigned as surgeon to Paris’s St. Martin Hospital. In 1870, when the Franco-German war broke out, he was a medical assistant-major and was sent to the army at Metz as ambulance officer. He took part in the battles of Gravelotte and Saint-Privat and in the siege of Metz where he was taken prisoner. At the end of the war the young surgeon returned first to Lille hospital and then to the St. Martin Hospital, where he took a particular interest in studying the infectious diseases of soldiers. In 1874 he was appointed, after competitive examination, to the Chair of Military Diseases and Epidemics at the École de Val-de-Grâce, previously occupied by his father. But in his new job Laveran found that teaching and administration precluded most research. Finally in 1878 these burdens were removed when he was transferred to Bône in Algeria and later to the military hospital at Constantine, Algeria.

In Constantine, Laveran was confronted with hospitals full of malaria. Whole platoons were decimated by it, and rarely could an entire squadron be assembled at once for active duty. New recruits succumbed with sickening regularity. Laveran conducted autopsies on patients who had died of ‘malignant fever’ (P. falciparum) and the blood and the internal organs like the the brain and spleen always showed the ‘black granular microscopic bodies’. Laveran followed these ‘black pigments’, first described by Lancisi and then by the German scientist Meckel in 1847. For two years Laveran struggled with the tissue specimen, but found nothing more than the ‘black pigments’. In desperation he decided to confine his search to the fresh blood of malaria patients, an extremely felicitous choice.

Still not knowing what he was looking for, Laveran began taking blood specimens from pinpricks in the fingers of sick soldiers. After spreading a droplet into a thin film on a glass slide, he would peer at it for hours through a small, crude microscope. He could easily find the tiny black granules that were already accepted without question as the result of malarial infection. But on November 6, 1880, while examining a fresh blood specimen taken from a new hospital arrival, he found pigmented spherical bodies of variable size possessing amoeboid movement (free or adherent to the red cells), non-pigmented corpuscles forming clear spots in the red cells and pigmented elements, crescentic in shape in addition to the melaniferous leucocytes. The moving object on the slide caught Laveran’s eye. Under high power, this proved to be a tiny malarial body wriggling vigorously. Laveran watched amazed as the little crescent-shaped object lashed about so energetically that an entire red blood cell jiggled. Even the pigment granules appeared to be in frenzied motion. This was made possible probably because Laveran had used wet blood films.

Instantly, Laveran realized that he had found the cause of malaria, a tiny, living organism. He identified it within the blood of 148 other patients out of a total of 192 examined. It developed, he observed, from a small, colorless structure one-sixth the size of a red cell, gradually growing as large as the cell and meanwhile forming pigment granules. The larger malarial parasites had a crescent shape with pigment granules arranged in a ring. These organisms, often quite active, would suddenly produce lashing, whip-like filaments.

From his observations, Laveran deduced that the large, crescent-shaped organism was the fully developed parasite or “perfect form,” as he called it. After growing over a period of days, imbibing nourishment from the red cell, the parasite could survive independently in the blood. The appearance of filaments represented the climax of the process. Tertian, quartan, and quotidian malaria, he believed, occurred during different stages in the parasite’s development.

In 1880, the technique of examination of the blood was very imperfect, which contributed to the confusion. Although it was impossible to classify accurately, certain resemblances to other micro-organisms put it in the same group as the protozoa. He named his protozoan as Oscillaria malariae.

On December 24, 1880 in Italy, Laveran communicated the identification of pigmented erythrocytic cells in 26 malaria patients. Laveran wrote a letter to the Academy of Medicine in Paris, communicating his discovery. [Laveran, A. 1880. A new parasite found in the blood of malarial patients. Parasitic origin of malarial attacks. Bull. mem. soc. med. hosp. Paris. 17: 158-164] The observations were quickly confirmed. Laveran reported them to a friend, Dr. E. Richard, stationed at Philippeville, a French Mediterranean military base fifty miles from Constantine. After finding the fully developed, wriggling parasite, Richard identified an even younger form than Laveran had seen, merely a tiny, colorless spot in the red cell. Laveran believed that the organism lived on the surface of the cell, but Richard correctly observed that it developed within the cell, growing larger and larger until it finally burst out.

But under the sway of bacteriology, the scientific community remained unconvinced about Laveran’s discovery. So powerful an influence was the new bacteriology that no one could believe the pigmented malarial bodies were the cause of malaria. This haematozoon did not resemble bacteria, was present in strange forms, and “was completely outside the circle of the known pathogenic microbes”. The arguments presented by Klebs and Tommasi-Crudeli for their “Bacillus malariae” had been accepted almost without question, and an Italian pathologist, Ettore Marchiafava, even claimed to have found the bacillus in several dead malaria patients. In 1882, Laveran went to Rome to look for these parasites in the blood of those infected with malaria in the Roman Campagna at the San Spirito Hospital and he confirmed his findings that the parasites that he had described were in fact the cause of malaria. He demonstrated the parasites to Marchiafava and Agnello Celli, but these two could not be convinced.

Major George Sternberg of the US Army, a bacteriologist of considerable standing, made bacterial cultures from the air, from mud, and from nearby marshes and no organism he found was capable of producing malaria in an animal. By 1881 he had shown positively that the Bacillus malariae of Klebs and Tommasi-Crudeli was not responsible for malaria.

Meanwhile, in 1884, Russian physiologist, Basil Danielewsky was able to observe parasites of malaria in the blood of wild birds. By 1884, Louis Pasteur became convinced of the soundness of Laveran’s observations.

In 1884, Marchiafava and Celli, while studying wet blood smears from malarious patients with the new oil-immersion lens, looked at unstained blood and saw a active amoeboid ring (trophozoite) in the red blood cells. They published this finding and named it Plasmodium, but did not refer to Laveran since they thought it was something different from what he showed them. The name chosen for the parasite by them turned out to be an incorrect one, since the organism is not actually a plasmodium. But the name stuck and the one suggested by Laveran lost out.

Dr. William Osler, an authority on blood microscopy, was also skeptical of Laveran’s theory. In 1886 he stated that the malarial bodies were nothing more than incidental findings. When his colleague, Dr. William T. Councilman, persuaded him to reconsider, Osler spent many hours looking at wet-blood films and confirmed Laveran’s findings with his own description of blood film examinations from 70 patients.

By 1885-86, Camillo Golgi, an Italian neurophysiologist and his pupils not only accepted and defended Laveran’s theory of a parasitic origin for malaria, but they also provided many new pieces of evidence and wholeheartedly threw their weight in support of Laveran.

Gradually, confirmative researches were published by scientists of every country and, in 1889, the Academy of Sciences awarded him the Bréant Prize for his discovery, putting a full stop to any doubts.

Maj. Laveran

Maj. Laveran

Laveran was also one of the first to suggest a role for mosquitoes in transmission of malaria. From extensive negative results searching for the parasite in samples of water, soil, and air, Laveran hypothesized that the parasite must undergo one phase of its development in mosquitoes and that the mosquito acted as a temporary host of the malarial parasite. He made an analogy with Manson’s mosquito-borne mode of transmission of the Filariasis. In 1894, he wrote about his ideas in a report to the International Congress of Hygiene at Budapest on the aetiology of malaria. He also noted that this opinion on the role of mosquitoes was considered by most observers at that time as not very likely. King, Robert Koch and Patrick Manson had also suggested that mosquitoes may be involved in the spread of malaria and this fact was later confirmed by Ronald Ross.

Laveran was a finest gentleman. He made the following observations about his work and its criticism:

“In 1878, after having completed my agrégation at the School of Military Medicine of the Val de Grâce, I was sent to Algeria and put in charge of a ward at the Bône Hospital. Many of my patients were suffering from malarial fevers and I was naturally drawn to studying these fevers of which in France I had observed only rare and benign forms.

…I had the opportunity to carry out autopsies on patients who had died from these pernicious fevers and to study melanemia- or the formation of black pigment in the blood of subjects suffering from malarial fevers. Melanemia had been described by several observers, but neither the constancy of this alteration in malaria, nor the causes for the production of the pigment had been determined.

… I was struck by the particular characteristics present in the pigment grains, particularly in the capillaries of the liver and the cerebrospinal centres and I sought to study- in the blood of patients suffering from malarial fever- the formation of the pigment. In their blood, I found leukocytes more or less coloured with the pigment, but besides melaniferous leukocytes, I found pigmented spheric bodies, of variable volume, with ameba-like movements, free or glued to erythrocytes, non pigmented corpuscles which made light spots in the erythrocytes; finally pigmented elements shaped like crescents retained my attention: I guessed then that these were parasites.

…In 1880, at the military hospital in Constantine, I discovered on the edges of the pigmented spheric bodies, in the blood of a patient suffering from malarial fever, thread-like elements resembling whips which were scurrying about with great vivacity, displacing neighboring erythrocytes; from the on, I had no further doubts as to the parasitic nature of the elements I had found; I described the main forms which the hemacytozoon of malaria took in notes which I submitted to the Academy of Medicine and the Academy of Sciences (1880-1882) and in a short treatise entitled:

The Parasitic Nature of Accidents of Impaludation, Description of A New Parasite Found in The Blood of Patients Suffering from Malarial Fever, Paris 1881.

The first results of my research were greeted with much skepticism.

In 1879, Klebs and Tommasi Crudeli had described by the name of Bacillus malariae a bacillus found in the ground and water of malarial sites and quite a few Italian observers had published works confirming the findings of these authors.

The hemacytozoon which I defined as the agent of malaria did not resemble bacteria; it was found in singular forms; in a word, it did not belong to the world of known pathogenic microbes, and many observers, not knowing where to classify it, found it easier simply to doubt its existence.

In 1880, techniques for examining blood were unfortunately far from perfect, a fact which contributed to drawing out discussions on the new hemacytozoon. Techniques had to be perfected and new methods of coloration invented in order that the structure of the hemacytozoon be shown up.

Studies which confirmed my findings, at first few in number, began to grow; at the same time, endoglobular parasites bearing a great resemblance to the hemacytozoon of malaria were being discovered in animals. By 1889, my hemacytozoon had been found in most malarial regions; it was no longer possible to doubt its existence, nor its pathogenic role.

Before myself, numerous observers had searched in vain for the agent of malaria; I too would have failed, had I been satisfied with examining the air, water, and earth of malarial sites, as had been practiced up to then; as a basis for my research, I took pathological anatomy and the study in vivo of malarial blood, and that is how I arrived at my destination.

… After having discovered the parasite of malaria in patients’ blood, there remained an important question to be solved: in what form did the hemacytozoon exist in the exterior environment and how did the infection come about? The solution to this problem required long and laborious research.

After having made futile attempts to detect the parasite in the air, water, and earth of malarial sites, and to cultivate it in the most varied of environments, I was convinced that the microbe existed outside the human body, in a parasitic state, and most probably in the shape of a parasite of mosquitoes.

I advanced this opinion as early as 1894 in my Treatise on malarial fevers and I came back to it on several occasions.

In 1894, in a report to the International Congress of Hygiene in Budapest concerning the etiology of malaria, I wrote: ‘The failure of my attempts to cultivate the hemacytozoon have led me to believe that the microbe of malaria lives in the outside environment in the form of a parasite and I suspect the mosquitoes which are so abundant in all malarial sites and which already play such an important role in the spread of filariasis.’

This opinion on the role of mosquitoes was considered at the time, by most observers, as highly unlikely.

Having myself left malarial countries, I was unable to verify the hypothesis I had advanced. It was Dr. Ronald Ross who had the merit of proving that the hemacytozoon of malaria and a hemacytozoon of birds very similar to the Hoemamoeba malariae went through several phases of their evolution in culicides and were spread by these insects.

R. Ross, whose admirable and patient research was very justly rewarded in 1902 by the Nobel Prize in medicine, was good enough to recognize in several of his writings that he had been usefully guided by my inductions and those of P. Manson.

Today, the transformations which the hematozoon of malaria undergoes in mosquitoes of the Anopheles types are well known and there are no more doubts possible as to the role of these insects in the spread of malaria.

… Before discovering the hemacytozoon of malaria, there was no known pathogenic endoglobular hemacytozoon ; today, the Haemocytozoa constitute an important family by the number of types and species and by the role that some of these protozoa play in human and veterinary pathology.

The discovery of these new pathogenic agents shed new and bright light on a great number of questions which had remained obscure up to then. The progress carried out shows once again how right is the expression formulated by Bacon: Bene est scire, per causas scire.”

In 1885 Laveran married Mlle Pidancet.

In 1884, he was appointed Professor of Military Hygiene at the École de Val-de-Grâce. In 1893, Laveran was elected a Member of the Academy of Sciences. In 1894, his period of office as professor having ended, he was appointed Chief Medical Officer of the military hospital at Lille and then Director of Health Services of the 11th Army Corps at Nantes. He had neither a Laboratory nor patients, but he wished to continue his scientific investigations. He now held the rank of Principal Medical Officer of the First Class and in 1896 he entered the Pasteur Institute as Chief of the Honorary Service.

From 1897 until 1907, he carried out many original researches on endoglobular Haematozoa and on Sporozoa and Trypanosomes, eventually identifying more than twenty new organisms. This work certainly enhanced his reputation as a scrupulous, perservering, wise investigator of perfect technicity. His special focus was on the trypanosomes and he published either independently or in collaboration with others, a large number of papers on these blood parasites. He successively studied: the trypanosomes of the rat, the trypanosomes that cause Nagana and Surra, the trypanosome of horses in Gambia, a trypanosome of cattle in the Transvaal, the trypanosomiases of the Upper Niger, the trypanosomes of birds, Chelonians, Batrachians and Fishes and finally and especially the trypanosome which causes the terrible endemic disease of Equatorial Africa known as sleeping sickness.

In 1907 he was awarded the Nobel Prize for his work on protozoa in causing diseases and he gave half the Prize to found the Laboratory of Tropical Medicine at the Pasteur Institute. In 1908 he founded the Société de Pathologie Exotique, over which he presided for 12 years.

He did not abandon his interest in malaria. He visited the malarious areas of France (the Vendée, Camargue and Corsica) and played a large part in the enquiry on the relationships between Anopheles and malaria in the campaign undertaken against endemic disease in swamps, notably in Corsica and Algeria.

In 1912, he became a Commander of the Legion of Honour. During the years 1914-1918, he took part in all the committees concerned with the maintenance of the good health of the troops, visiting Army Corps, compiling reports and appropriate instructions. He was a member, associate or honorary member of a vast number of learned societies in France, Great Britain, Belgium, Italy, Portugal, Hungary, Rumania, Russia, the U.S.A., the Netherlands Indies, Mexico, Cuba and Brazil.

laveransrLaveran did not, for 27 years, cease to work on pathogenic Protozoa and the field he opened up by his discovery of the malarial parasites has been increasingly enlarged. Protozoal diseases constitute today one of the most interesting chapters in both medical and veterinary pathology.

Those who were closely acquainted with Laveran knew that underneath a somewhat distant and reserved exterior there lay hidden a very sensitive soul. His character was invariably upright, his speech slow and thoughtful, enhanced by precision and free of solemn gestures. His physionomy, the clarity of his gaze reflected the serenity and honesty of his intelligence. He surrounded his research with silent discretion up until the time he decided to publish his results.

Journalists knocked vainly at this door. He never gave any interviews. And thus the public hardly knew of him and he could not have cared less!

For a long time, he suffered from the indifference, hostility or disdain with which his discoveries were met. The ignorance and ingratitute of military leaders who obstinately barred the way for his reaching the higher ranks of the army were particularly painful for him.

But he had his revenge, and what a glorious revenge! The Pasteur Institute offered him a laboratory, the Academy of Sciences, the Royal Society of London, all the scientific associations of the world sought to welcome and honour him. The Carolin Institute awarded him the Nobel Prize and the Academy of Medicine wished him to preside their one hundredth anniversary!

Until a few weeks before his death, although he already had no more illusions as to the fatal outcome of the illness which had struck him, he was still working, keeping in touch with his laboratory- to which he no longer had the strength to go- through the faithful Léon Breton and his student, Dr. Franchini. On May 18, 1922, he succumbed to his prolonged illness.

Sources:

  1. http://stevenlehrer.com/explorers/images/explor1.pdf
  2. Obituary of Prof. A. Laveran. Bulletin de la Société de pathologie exotique, 1922, vol 15, n°6. Available at: http://www.pathexo.fr/pages/english/ObitLav.html
  3. http://www.geocities.com/med_for222nat/laveran.html
  4. Alphonse Laveran. Protozoa as Causes of Diseases. Nobel Lecture, December 11, 1907. Available at http://nobelprize.org/medicine/laureates/1907/laveran-lecture.html
  5. http://nobelprize.org/medicine/laureates/1907/laveran-bio.html (From Nobel Lectures, Physiology or Medicine 1901-1921, Elsevier Publishing Company, Amsterdam, 1967)
  6. http://crishunt.8bit.co.uk/alphonse_laveran.html
  7. http://www.todayinsci.com/cgi-bin/indexpage.pl?http://www.todayinsci.com/L/Laveran_Alphonse/Laveran_Alphonse.htm

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One Response to Laveran

  1. Dr.T.Ravinder Rao says:

    Great.A hero among medical scientists.

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