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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.
See
History Of Scientific Discoveries On Malaria |
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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.
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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.
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Laveran 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.
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