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Quinine, a toxic plant alkaloid made from the bark of the cinchona
tree in South America, was used to treat malaria more than 350 years
ago. Jesuit missionaries in South America learnt of the anti-malarial
properties of the bark of the cinchona tree and had introduced it
into Europe by 1630s and into India by 1657. In the mid-1800s, the
Dutch brought cinchona seeds from Peru and established cinchona
plantations in Java (Indonesia) and soon had a virtual monopoly
on quinine.
Malaria
About a century ago, of the British Army in India,
amounting to about 1,78,000 men, close upon 76,000 men were admitted
into hospitals for malarial fever in the year 1897. In this single
year, the mortality from fever among the civil population in India,
amounted to a total of more than five millions. Today, malaria is
considered to be one of the most important parasitic diseases worldwide.
40 per cent of the world’s population lives in malaria endemic
areas. 500 million clinical cases and about 3 million deaths are
reported each year. In Africa, malaria deaths may account for 10
per cent of the overall annual mortality in children under 14. The
worldwide distribution of malaria is shown in Figure 1 based on
1976 statistics. It reveals the presence of malaria in most of the
world’s developing regions and its notable absence in arid
or mountainous areas where mosquitoes usually do not breed. Malaria
parasites causing malaria are prevalent in regions lying roughly
between latitudes 60° N and 40° N. It is widespread in tropical
and temperate countries.
Malaria, one of the
world's most persistent diseases, affects 500 million people
- many of whom suffer recurrent attacks - and kills 3 million
each year. Almost all of the victims live in moist, tropical
regions where disease-bearing mosquitoes breed freely. Attempts
to control the spread of malaria by means of pesticides have
not been successful, and in the 1970s there was a resurgence
of the diseases, carried by mosquitoes immune to the pesticides.
This map, based on 1976 statistics, reveals the presence of
malaria in most of the world's developing regions-and its
notable absence in arid or mountainous areas where mosquitoes
usually do not breed (Figure). |
Till over a century ago, the popular view had been
that malaria was caused by bad air (mal aria - Italian for bad air)
or contaminated water. However, only in 1880, the first true sighting
of the malarial parasite was made in Algeria by a French Army physician,
Charles - Louis - Alphonse Laveran (1845-1922) while viewing blood
slides of infected soldiers under a microscope. He showed that patients
with malaria carried a protozoan parasite (called plasmodium), in
their blood, and doctors began suspecting that mosquitoes spread
the parasite causing the malarial infection. Laveran’s discovery
was, however, rejected by the medical community and it was not until
1886 that his discovery was accepted by Italian scientists, who
were the leaders in the field at the time. We may remark here that
it was in 1882 that the mosquito transmission hypothesis was first
made as a result of the association between the presence of mosquitoes
and the occurrence of malaria - a case of guilt by association!
By this discovery, the name of Laveran has forever become renowned
in the history of malaria.
Malaria
How is it caused?
Malaria is a serious disease caused when a parasitic single
celled organism, called plasmodium, enters the red blood cells.
It is transmitted by several different species of mosquitoes
of the genus anopheles that includes many that are carriers
of the malarial parasite (plasmodium). The most severe form
of malaria is caused by the parasite plasmodium falciparum.
Generally, mosquitoes carrying malaria are found in tropical
and sub-tropical climates.
Symptoms of malaria
After an incubation period of about 2 -
5 weeks, there is a sudden attack of shivering followed by
a high fever of about 1040F. This is often accompanied by
headache and vomiting that lasts for several hours. These
symptoms may occur at interval of 2 - 3 days, depending on
the type of malaria. If the disease is not treated, the symptoms
may recur at irregular intervals and even for many years.
How is malaria diagnosed and treated?
Though periodic bouts of shivering and high
fever are symptomatic of malaria, only a blood examination
can reveal the presence of malarial parasites. Initial treatment
is with the drug chloroquine. Unfor-tunately, the parasite
plasmodium falciparum is often resistant to chloroquine and
many other drugs .
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The Mosquito Trail
In the early days, research about malaria was
chiefly based on Laveran’s discovery. It helped gain knowledge
of the different forms of the malarial parasite in blood. It was
found that it differed in the special forms of the disease. The
relation between the parasite and the red blood corpuscles, in which
it is chiefly to be found, was established. The Italian investigator
Camillo Golgi (1843 - 1926) revealed the remarkable fact that the
periodicity of the malarial attacks depended on the appearance of
new generations of the parasite in the blood. Moreover allied parasites
in the blood of several mammals and birds also were found.
The important question, previously mentioned,
as to possibility of the malarial parasite living outside the body,
and its way of obtaining entrance into the blood remained unanswered.
Fore some reasons, among others owing to various facts that were
known concerning other parasites of an animal nature, it was supposed
that the malarial parasite in some way leaves the blood so as to
exist in some form in nature, probably as a parasite of some other
being. As nothing indicated that the parasite was to be found in
the secretions or excretions, the supposition lay near at hand,
that suctorial insects would assist in carrying the parasite to
a place, where it had to pass the aforementioned part of its life-cycle.
Attention was therefore directed to the mosquito, which was thus
supposed to spread the malarial infection. The importance of the
mosquito in this respect was proved. In this case, as in several
others, tradition anticipated science; it is even said, that Negroes
in the East-Africa use the same name for the mosquito and for malaria.
The mosquito theory of malaria was introduced
to science by A.F.A. King in 1883. The theory, however, remained
a conjecture without other evidence than some suggestions given
by epidemiological observations. The attempts made in Italy around
that time with the view of examining the theory experimentally,
and, eventually, proving it to be true, gave results that seemed
anything but encouraging; being far more likely to prevent the investigators
from following this line.
A person of great merit concerning the solution
of the problem was the English Investigator, Patrick Manson. It
was a change in the appearance of the parasite, which was sometimes
observed to occur, as the blood is shed, that Manson especially
regarded as the first stage of its life outside the body. This phenomenon
was afterwards shown by the American pathologist Mac Callum to imply
an act of reproduction of the parasite. Manson was moreover guided
by his experience regarding another parasite of the blood, a little
worm, filaria, the transference of which from one part of its life-cycle
to another he had found effected by the mosquito, and more particularly
by special species of the mosquito. By his views set forth on malaria,
and by exciting expectation that the solution of the malaria problem
was to be found in the direction he indicated, Manson gave an impulse
to the further testing of the mosquito-theory and at last to its
being established. Manson, who lived in England, had no opportunity
of taking up the experimental work of the problem. The solution
came from India.
Ronald Ross
It was at this juncture that Ronald Ross entered
the arena. He was born in Almora, India, on May 13, 1857 - the year
of the great Indian uprising - as the son of Sir C.C.G. Ross, a
general in the English Army. Ross received an English dame and boarding
school education. Subsequently he studied medicine at St. Bartholomew’s
Hospital, London, but with little enthusiasm. Although he had bowed
to his father’s wish that he not become an artist, his passionate
interest in the arts took up much of his time. Ross published plays,
short dramas, romances, fables, and poetry. He was married in 1889
to Rosa Bloxam and had two sons and two daughters. He was elected
to the Royal Society in 1901 and knighted in 1911.
MALARIA'S CONQUEROR
and the mosquito he defeated are affectionately caricatured
in a 1908 carton published by a newspaper in the British colony
of Mauritius. The colony's hero was Sir Ronald Ross, A British
Army surgeon, who had proved nine years earlier that malaria
was transmitted by the bit of the Anopheles mosquito, and
not by malaria (Italian for "bad air"). Where malaria
had spread with increasing ferocity for 40 yerars, Ross ordered
that the mosquito- breeding swamps to drained, and thus halted
the epidemic (Figure). |
Apart from the arts, Ross had an abiding interest
in mathematics, much of his self-education in the subject being
undertaken while he was serving in the Indian Medical Service (1881-1888).
Ross became more and more conscious of medical problems the longer
he remained in India. Later he wrote: “I was neglecting my
duty in the medical profession. I was doing my current work, it
was true; but what had I attempted towards bettering mankind by
trying to discover the causes of those diseases which are perhaps
mankind’s chief enemies?”
In India, Ross succeeded in demonstrating the
life cycle of the parasites of malaria in mosquitoes. Ross collected
and identified various kinds of mosquitoes, dissected their guts
and in August 1897 found his quarry in Anopheles mosquito that had
just fed on a malaria patient. December 18, 1897 issue of the British
Medical Journal reported that Dr. Ronald Ross discovered malaria
cysts containing sporozoites (the same parasite Laveran had seen
in the blood of his patients) in the stomach wall of anopheline
mosquitoes that fed on a malaria patient. By July 1898, malaria
transmission through the mosquito was established.
In 1899, Ronald Ross joined the Liverpool School
of Tropical Medicine. He was immediately sent to West Africa to
continue his investigations, and there he found the species of mosquitoes
which convey the deadly African fever. In 1901, Ross was elected
a Fellow of the Royal College of Surgeons of England and a Fellow
of the Royal Society. In 1926, he assumed the post of Director in
Chief of the Ross Institute and Hospital of Tropical Diseases and
Hygiene, which had been created by the admirers of his work. During
his active career, Ross’ interest lay mainly in the initiations
of the measures for the prevention of malaria in different countries
of the world. He carried out surveys, initiated schemes, and established
organisations for the prevention of malaria in several countries
and places including the planting industries of India and Sri Lanka.
Probably his greatest contribution was the development of mathematical
models for the study of the epidemiology of malaria - that is, the
causes, distribution and control of the diseases. Ronald Ross received
the Nobel Prize for Physiology or Medicine in 1902 for his monumental
work.Ronald Ross died in London on 16 September 1932 at the age
of seventy five.
Mosquito Trail Continued
Unlike most of his colleagues in the Indian Medical
Service, Ross was research-minded. In 1888, during his first furlough
in England, he earned the newly established Diploma of Public Health
and took a course in bacteriology. On returning to India, he studied
malaria, initially believing that it was caused by intestinal auto-intoxication.
During Ross’s next furlough in England (1894) his successful,
far-reaching malarial studies were initiated. This was due in large
measure to the influence of Patrick Manson, for three reasons a
key figure in Ross’s contribution to the unravelling of the
life history of the malarial parasite. First, Manson demonstrated
convincingly to a skeptical Ross the correctness of Alphonse Laveran’s
pioneering observations of 1880: that the blood of malarial patients
contained pigmented bodies of parasites.
Second, Manson propounded a theory that mosquitoes
transmitted malaria. Third, through an extensive exchange of correspondence
with Ross, he helped to sustain the latter’s researches in
India during more than three years of difficulties that arose not
only from problems of technique and of obtaining volunteer patients,
but also from regimental duties and unsympathetic superiors.
In essence the problem Ross set himself - to prove
Manson’s hypothesis that mosquitoes transmitted malaria -
was enormous, for he had to contend with two variables : a variety
of mosquitoes and a variety of parasites. The questions were which
mosquito was the vector and which parasites were the malarial parasites
(now known to be species of plasmodium, a protozoan involving two
different hosts in its life cycle. There are more than hundred species
of plasmodium, but only four species have human as their natural
host. See box)
The main points in Ross’s contributions
to the problem during 1895 - 1898 can be summarized as follows:
First, Ross demonstrated that volunteers who drank water contaminated
with infected mosquitoes (including larvae) failed to contract the
disease. This, along with his earlier doubts that aerial and water
contamination provided a ready explanation for the epidemiology
of malaria, did much to direct his attention to the possibility
that transmission might be via mosquito bites ( a point of view
expressed by A.F.A.King in 1883). Ross apparently was ignorant of
King’s work until 1899; and in fact he met continual problems
because of a shortage of scientific literature in India, above all
in connection with identifying and classifying mosquitoes.
Life cycle of plasmodium falciparum
The life cycle of all Plasmodium species is complex. Infection
in humans begins with the bite of an infected female Anopheline
mosquito. Sporozoites released from the salivary glands
of the mosquito enter the bloodstream during feeding quickly
invade liver cells (hepatocytes). Sporozoites are cleared
from the circulation within 30 minutes. During the next
14 days in the case of P. falciparum, the liver-stage parasites
differentiate and undergo asexual multiplication resulting
in tens of thousands of Merozoites which burst from the
hepatocyte. Individual merozoites invade red blood cells
(erythrocytes) and undergo an additional round of multiplication
producing 12-16 merozoites within a schizont. The length
of this erythrocytic stage of the parasite life cycle depends
on the parasite species. The clinical manifestations of
malaria, fever and chills, are associated with the synchronous
rupture of the infected erythrocyte. The released merozoitesgo
on to invade additional erythrocytes. Not all of the merozoites
divide into schizonts, some differentiate into sexual forms,
male and female gametocytes. These gametocytes are taken
up by a female anophylis mosquito during a blood meal. Within
the mosquito midgut, the male gametocyte undergoes a rapid
nuclear division, producing 8 flagellated microgamtes which
fertilize the female macrogamete. The resulting ookinete
traverses the mosquito gut wall and encysts on the exterior
of the gut wall as a oocyst. Soon the oocyst ruptures, releasing
hundreds of sporozoites into the mosquito body cavity where
they eventually migrate to the mosquito salivary gland (Figure).
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Second, Ross’s studies on the parasites in
mosquitoes involved learning how to identify mosquitoes and to dissect
their internal organs. From the beginning Ross was especially concerned
with the “motile” parasitic filaments found in mosquito
stomachs. The question was what happened to them. While he failed
to recognize that the filaments were gametes (a point first appreciated
by W. G. Mac Callum in 1897), Ross’s supposition that they
developed into another stage stood him in good stead, for it ensured
that he spaced out his examination of individual mosquitoes from
groups that had fed on malarial patients.
Even so, it was not until 20 August 1897 that
he observed in the stomach wall of a type of mosquito he had not
hitherto encountered (a malarial vector anopheles, rather than the
Culex and Stegobium he had been investigating for over two years)
a cyst containing granules of blank pigment similar to the pigmented
bodies initially observed by Laveran. 20 August 1897 was called
“Mosquito Day” by Ross.
Third, owing to the administration of the Indian
Medical Service, Ross was unable to continue his studies on this
stimulating find, which he had immediately recognized, should lead
him to unravel the complete life cycle. Some months later, however,
he was able to study malaria in caged birds (Avian malaria) and
to demonstrate the parasite life cycle, including stages in mosquito
salivary glands. He also was able to demonstrate that mosquitoes
could transmit malaria directly from infected to healthy birds.
Ross’s discoveries into malaria were immediately
followed by a series of important works. The Italian investigator,
Grassi , in association with his colleagues, Bignami and Bastianelli,
proved that the human malarial parasite not only in its early stage,
already detected by Ross, but also in its further development undergoes
the same evolution that Ross described for the growth of the avian
malarial parasite in the body of the mosquito. Grassi also precisely
indicated the species of mosquito that are of import for the malaria
of man .
Manson and his characteristic modesty
In 1890, Manson had set up a practice in London and was
appointed Physician to the Seamen’s Hospital, where
he had access to many cases of tropical disease. He carried
out prolonged observations on the “exflagellation”
of malaria and, in a paper published in 1894, postulated
that the process was a normal part of the life cycle of
the parasite in the stomach of the mosquito. In the same
year he met Ronald Ross, with whom, after showing him the
malaria parasite, he spent long hours discussing the mosquito-malaria
theory. Largely as a result of pressure on the India Office
brought to bear by Manson, Ross was dispatched to India
the following year to investigate the theory. Manson’s
advice was to “follow the flagellum”, and Ross
soon succeeded in observing exflagellation in the stomach
of the mosquito. But the problem of following the parasite
into the tissues of the mosquito, of which only one species
is suitable for development, proved to be a Herculean task.
Throughout the months of investigation that followed, Manson
maintained a continuous correspondence with Ross. In August
1897 Ross dissected a new type of mosquito (Anopheles) that
had fed on a malaria patient, and in it he found pigmented
round bodies on the stomach wall. The pigmented bodies were
sent to Manson, who confirmed their significance. Soon afterward
Ross was removed to an area where human malaria was absent,
and there he applied himself to the study of Proteosoma,
a malaria parasite of sparrows. From this study he was able
in 1898 to describe its complete life cycle in the mosquito.
The discovery was announced by Manson at a meeting of the
British Medical Association in Edinburgh. Ross fully acknowledged
the part played by Manson; but Manson, with characteristic
modesty, disclaimed any credit save that of having “discovered”
Ross.
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Life Cycle of Plasmodium
Plasmodium spends its life cycle in two hosts
- Man and Mosquito (anopheles). Man is the primary host in whom
it causes the disease and harbours the adult stages of the parasite
Mosquito is the secondary or intermediate host.
It is also known as the vector or the carrier of the disease as
it carries the parasite (plasmodium) from an infected host to a
fresh human host. Having two hosts, Plasmodium ensures continuance
of its existence in the event of death of any one host. Therefore
the complete life-cycle of the human malaria parasite embraces i)
a period of development and infection in man, and ii) a period of
development in the mosquito. But in these two hosts the life cycle
shows three phases.
Malaria Parasites
Malaria is caused by PLASMODIUM, a Protozoan involving two
different hosts in its life cycle. There are more than hundred
species of Plasmodium, but only four species have human as
their natural vertebrate host. They are :
P. vivax:
i. Widely distributed.
ii. New generation of merozoites formed every 48 hours causing
fever.
iii. Incubation period is 10 days.
P. ovale :
i. Found in West Africa and South America.
ii. Fever comes every 48 hours (due to the formation of new
generation of merozoites)
iii. Incubation period is 14 days.
P. malariae :
i. Found in both tropics and temperate zones but not very
widespread.
ii. Fever comes after every 72 hours.
iii. Incubation period varies from 27 - 37 days.
P. falciparum :
i. Common in tropics, including India.
ii. Most dangerous as it causes almost continuous fever but
the course is shorter and without relapses.
iii. Incubation period is 10 days.
The arthropod hosts are females of certain species of Anopheles
mosquito. There is no animal reservoir for any of these human
parasites except possibly chimpanzees for P. Malariae. Malaria
therefore cannot be acquired in uninhabited regions, for malaria
to thrive there must be infected human beings and plenty of
man-biting Anopheles, and easy contact between the two. Plasmodium
also parasitizes lizards, birds and mammals but these differ
from human malaria parasite.
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Schizogony - a cycle of growth
and asexual multiplication in the liver cells and erythrocytes of
man.
Gamogony - sexual cycle which begins in man and
is completed in the stomach of anopheles.
Sporogony -A cycle of asexual multiplication or
sporogony in the stomach of anopheles. Let us consider the three
stages in some detail.
Schizogony
When an infected female Anopheles bites man for its blood meal (Figure)
it inoculates the malarial parasites into the human blood alongwith
the saliva. This infective stage is a minute sickle shaped sporozoite
which enter in thousands and remain in the blood for about half
an hour. After that they enter the parenchymatous cells of the liver
to escape from phagocytic white blood corpuscles and multiply in
number. Basically schizogony is a phase of growth and multiple fission
to form the merozoites. It is subdivided into the following phases:-
Sporozoites enter the liver cell, enlarge to form
a schizont which divides to form about 1000 small spindle shaped
merozoites called cryptozoites. They are immune to medicine and
also to the resistance of the host. This is called the pre-erythrocytic
phase.
Cryptozoites (merozoites) enter new liver cells,
grow into schizonts which again divide to form metacryptozoites
(merozoites). This phase may continue in fresh liver cells or attack
erythrocytes. Those which attack the erythrocytes are called metacrypto-merozoites.
This is called the exo-erythrocytic phase.
On entering the RBC, the merozoites begin to feed
on the corpuscles to form the adult stage or the trophozoite. The
trophozoite grows further at the expense of the corpuscles to form
the signet ring stage, amoeboid stage and schizont respectively.
These are characterized by the presence of haemozoin granules and
Schuffner’s dots.he schizont ruptures to liberate the schizozoites
(merozoites) and toxins which cause the periodic paroxysms (bouts
of chills and fevers) and other symptoms as the cycle is repeated
every 48 hours in new erythrocytes in case of P.
Vivax - a species of plasmodium.
This is called the Erythrocytic phase.
Sometimes during the post erythrocytic phase, some merozoites produced
in erythrocytic schizogony reach the liver cells and undergo schizogonic
development in liver cells.
Gamogony
It is the sexual phase beginning in man but completed
only in the female Anopheles. Some merozoites enlarge and produce
pigment to form the gametocytes. Megagametocyte or female gametocyte
is round with food laden cytoplasm and a small eccentric nucleus.
Microgametocyte or male gametocyte have clear cytoplasm and a large
central nucleus.
The gametocytes can develop further only in the
body of a mosquito where suitable temperature is available.
When mosquito sucks the infected blood, the corpuscles
are dissolved but the gametocytes are not digested. Microgametocytes
undergo exflagellation i.e. the nucleus divides into 4-8 nuclei
around which cytoplasm collects to form long flagellated structures
called microgametes which break and begin to swim in the stomach
of the mosquito.
In the megagametocyte the nucleus divides into
two, one of which projects out as the polar body. Fertilization
takes place to form zygote. Sexual cycle is completed in any kind
of mosquito but further development is possible only in the female
Anopheles.
Sporogony
Those zygotes which penetrate the stomach wall
undergo further development or else they elongate and pass out with
the faeces as the ookinese or the dying stage. The zygote comes
to lie below the outer epithelium where it becomes encysted to form
the oocyst. The oocyst absorbs nourishment, grows about 5 times
in size. It’s nucleus divides repeatedly to form many nuclei
and cytoplasm develops large vacuoles called zoitoblasts. Nuclei
arrange themselves around the margin of vacuoles. Each nucleus acquires
some cytoplasm to form a slender spindle shaped sporozoite. Later
the sporozoites break loose and form a tangled mass in the oocyst.
About 50 wart like oocysts are formed in the stomach
of a single mosquito and each oocyst may have 10,000 sporozoites.
The sexual phase takes about 10-21 days in the mosquito. When oocysts
burst, sporozoites are liberated and reach the salivary glands of
the mosquito. Thus the sporozoite is the infective stage which reaches
fresh host when it bites a man. Four species of Plasmodium cause
malaria in man but their life-histories are very much alike with
minor differences (see Box).
| Nobel Prizes awarded for
work on Malaria |
| Here is a list of Nobel Prizes awarded for work
on Malaria or related topics. |
| 1902 |
Ronald Ross |
Great Britain |
in Physiology Medicine for his work on malaria,
by which he has shown how it enters the organism and thereby
has laid the foundation for successful research on this disease
and methods of combating it |
| 1906 |
Camillo Golgi |
Italy |
in Physiology Medicine for their work on the
structure of the nervous system |
| |
Santiago Ramón y Cajal
|
Spain |
-do- |
| 1907 |
Charles Louis Alphonse Laveran |
France |
in Physiology Medicine for in recognition of
his work on the role played by protozoa in causing disease |
A Return Engagement
In the heydays of the war on malaria - especially
from the World War II through 1970s, widespread DDT spraying campaigns
were organised including in India to stifle the annoying blood suckers.
Larvicides and insecticides were used to kill mosquitoes before
they could carry the parasite between the victims. In fact, once
upon a time, malaria seemed destined for the history books, since
it was supposedly caught in a pincer attack. But, DDT played
havoc with the environment - it killed the birds and beneficial
insects as well as anopheles mosquitoes. Further, a cheap,
plant derived medicine chloroquine was available to kill parasites
before they gained a foothold in their victims.
Then nature took over
With a little help from modern ecological disturbances and tight
government budgets:
Most important species of malaria vectors (i.e. agents - mosquitoes
in this case) evolved resistance to one or more insecticides.
Malaria parasites in particular plasmodium falciparum, evolved resistance
to chloroquine and then to several successor drugs.
Increases in travel and international trade moved drug-resistant
parasites around the globe.
As mosquito-control efforts expanded, they grew more expensive,
forcing some governments to abandon them.
The unfortunate result was a resurgence of malaria.
There were major programs to control malaria, and they were quite
successful. But the need to use more expensive insecticides over
a broader range meant they were not sustainable.
Managing the scourge
Indeed, World Health Organisation (WHO) had initiated
strategies for the global eradication of malaria in the mid-1950s.
But, in 1960s, chloroquine resistant strains of plasmodium falciparum
had arisen. This was the result of over usage and probably under
dosage of chloroquine. At the time, there were no drugs to treat
chloroquine-resistant malaria except the ancient, quinine. Quinine
has now been completely synthesized, its synthetic analogue is called
mefloquin. A “new” anti-malarial is a drug called Qinghaosu
that is derived from the sweet wormwood (Qinghao) plant (genus Artemisia).
It has been used in China for more than two thousand years to treat
fevers associated with malaria. The drug has been shown to be effective
in the treatment of the most deadly forms of falciparum malaria
and has been effective against strains of plasmodium falciparum
that are solidly resistant to chloroquine.
In 1967, WHO realized that the global eradication
of malaria was impossible for a variety of reasons and the focus
shifted to control of the deadly disease. Since the idea of eradicating
mosquitoes was not realistic, the efforts were directed towards
the reduction and management of their population below the threshold
that would cause disease. (It may be remarked that besides malaria
and filaria, the deadly dengue fever is also spread by mosquitoes
belonging to a different species, viz. Aedes Aegyptes).
Only a combination of the following measures would
help control the scourge of mosquitoes:
- Public Education to explain to the people that some disease
carrying mosquitoes breed in puddles of water, air coolers, tyres
and other artificial containers, including flower pots around
the house.
- Behavioural controls like sleeping under mosquito nets - preferably
soaked in insecticide.
- Chemical controls with focussed use of less hazardous insecticides.
- Biological controls through introducing organisms that eat
or otherwise harm mosquitoes, or their larvae.
We have come a long way since Ronald Ross discovered
malaria parasite in the gut of the female anopheles mosquito. Though
the cause of malaria was discovered nearly a century ago by him,
the scourge of the mosquito still persists. Mosquitoes are back
with vengeance, and its guest plasmodium falciparum has not only
developed resistance to quinine, but continues to develop strains
resistant to even newer drugs. This war is continuing. We know how
malaria is caused, but we have yet to develop strategies and means
to control the spread of the disease. It is imperative that we channelise
our efforts in controlling and managing the mosquito menace, just
the way Ross did throughout his life.
References
- World Book Medical Encyclopaedia, World Book, Inc. 1998 An
up-to-date resource on Medicine, Health and Diseases.
- The Biographical Dictionary of Scientists Edited by Roy Porter,
Second Edition, Oxford University Press 1994 Gives brief accounts
of lives of scientists and their work.
- Dictionary of Scientific Biography Vol. IX & XI Editor-in-chief
Charles Coulston Gillispie Charles Scribner’s Sons, New
York 1975 A wonderful resource in 14 volumes.
- http://www.nobel.se official website of the Nobel Foundation
A treasure house on Nobel Laureates.
- Grzimek’s Animal Encyclopedia Vol. 2 Insects Van Nostrand
Reinhold Company 1969 Editor-in-Chief Dr. Dr. h.c. Bernhard Grzimek
A great resource in 13 volumes.
- Health and Disease Rene Dubos and Maya Pines Second Edition.
Time - Life Books, Hong Kong, 1984 Profusely illustrated and lucidly
written with text followed by a picture essay supplementing the
text.
- Surolia V Malaria - how to remove plaques and parasites D.
Balasubramanian The Hindu, March 1, 2001
Fighting the War Once Again
The National Malaria Health Programme in
the early 1950’s was a vigorous national health effort.
Combing the length and the breadth of the country, the health
workers sprayed DDT and other insecticides so as to wipe out
mosquitoes that bred in stagnant pools of water, and also
distributed quinine pills house to house. In the 1960’s,
the war against malaria appeared to have been won. But, malaria
returned with greater force - not just in India, but the world
over. The war is being fought once again. 40 per cent of the
world’s population lives in malaria endemic areas, 500
million clinical cases and about 3 million deaths each year
thanks plasmodium falciparum! Plasmodium has resurfaced in
mutant strains that are resistant to quinine, and its more
potent cousins, chloroquine and mefloquine. Other strains
of the parasite, like plasmodium vivax hit at the brain and
the central nervous system.
What could be the strategy then to wipe
out malaria? One could attempt to attack the parasite by targetting
some processes or metabolic paths crucial for its survival,
or make a vaccine that can be inoculated into us developing
immunity against it. Alternatively, spray insecticides to
kill mosquitoes, and take steps not to allow stagnant pools
of water to collect where mosquitoes breed. Thus, these are
the broad strategies to fight malaria - hit at the parasite
through drugs that disable it, develop a vaccine that offers
us immunity against it, and target the mosquito which is the
carrier of the parasite, by insecticide spray and removing
its breeding grounds. Let us consider them briefly.
Some people are trying clever strategies
on mosquitoes. These include genetically engineered mosquitoes
in such a manner that they become unable to carry the parasite
within, or shuffle the genes of the mosquito in such a manner
that it would kill the rider within - called the transposon
technology. There are also attempts to make the mosquitoes
sterile by exposing them to raidation, and then unleash millions
of these mosquitoes in the breeding grounds and let them mate.
Over 5-6 generations, the population could be wiped out.
There are attempts to make vaccines against
malaria, in our country as well as in other parts of the world.
Each group looks at what it considers to be an essential component
in the assembly of the parasite or body chemistry, and using
this component as the antigen, and tries to make a vaccine
that would produce the desired antibody. In our country, the
work is on at ICGEB, New Delhi, and CDFD, Hyderabad. Since
as of today, there is no malaria vaccine, we await the result
from these labs with much hope.
The third front is the development of drugs
against the parasite. In earlier times, drugs were identified
and developed empirically. Native medical practice and folk
tradition were of occasional help. This is how quinine was
found to be useful. However, the malaria parasite lives on
human blood and liver where it runs through its entire life
cycle. It degrades the proteins of our red blood cell and
lives on the digested soup. While doing so, it needs to watch
out for the iron-containing component of the red cell hemoglobin,
called heme, which can puncture holes in the parasite’s
cells and leak them to death. The parasite packages off the
heme as safe garbage in a lump of a pigment called hemozoin.
(It is this pigment that serves as the tell-tale sign of the
presence of the parasite in our body). The continuous playing
out of its life cycle between the tissues of the body makes
the task of containing the parasite difficult. The drug we
use should not be toxic to the liver, should not cause anemia
or blood loss, and should target the parasite alone and not
the surroundings of the zone that it colonizes. As it goes
through its drama of devastation, it changes shape, size,
the surface coat and the biochemical strategies of its survival.
The researcher who wishes to devise an effective antimalarial
drug needs to address this issue of multiple avatar or reincarnation
of the As noted earlier, quinine had lost its effectiveness
over the years in many parts of the world, since the plasmodium
parasites have developed genetic strains or variants resistant
to it. Better drugs of the quinine class have been developed
over the last 50 years, notably chloroquine and mefloquine,
by tinkering with the chemical structure of the parent quinine.
Both have been widely effective and popular. Soon enough,
chloroquine resistant strains of the parasite emerged, and
some groups tried to attack this problem by devising a combination
drug called Fansider (also called PM/SD). Strains resistant
to this drug too emerged! Now three other drugs are suggested
- one of them, called holopantrine, is effective against PM/SD
resistant strains. In the meantime, two products coming out
of Chinese medicines have proved useful - artemesinin, a plant
product and the other being pyromaridine, but the action of
the latter is unknown as of now.
Parasites breed fast and prolifically, these
alongwith the feature adaptive mutations, makes the emergence
of strains resistant to any newly introduced dru a frustrating
reality. how does one overcome this difficulty and attempt
to conquer disease of this kind? Namita Surolia of Jawahar
Lal Nehru Centre for Advanced Scientific Research, Bangalore,
and Avdesh of Indian Institute of Science, Bangalore (Namita’s
husband) argued that no matter what mutations or strains there
may be - all of them must share some inescapable physological
or biochemical features, mutations in which would be lethal
and not let the parasites survive. It is these vital processes
that should be identified and chosen as drug targets. Very
recently, the couple has been able to identify one such target
feature. Organisms like plasmodium parasites are not fully
competent and self-sufficient in their fatty acid production
which are important structural materials and energy sources
for them. They rely symbiotically on organelles called apicoplasts
residing in their cellular compartment; for some enzymes needed
for the process. Now, these organelles could be thought of
as drug targets. This is what Namita and Avdesh did in their
quest for an effective anti-malarial drug. They reasoned that
parasites cannot afford to bear any mutation in their apicoplast;
it is too vital an organelle to become inefficient or disabled!
Next, having realised that the apicoplast aids in making fatty
acids for use by the parasites, they started looking for inhibitors
of enzymes that catalyse the synthesis of fats and fatty acids.
One such inhibitors is the antibiotic Triclosan. Incidentally,
Triclosan is used as a broad spectrum/antimicrobial in pastes,
mouth wash, shampoo and so forth.
Surelias tested the effect of Triclosan
on the growth of P. falciparum and found that it arrested
the growth of the parasite at concentrations as low as one
milligram of the stuff in 3 litres of the medium! The discovery
by the Surolia couple that Triclosan is an antimalarial drug
has been well secured. However, they warn that Triclosan should
be used judiciously, or in combination with other antimalarials,
so as to avoid the problem of resistance currently seen with
drugs like chloroquine. They also found that another antibiotic
Cerulenin acts synergistically with Triclosan. Indeed, this
discovery of Surolias could pave the way for developing more
patent analogues of Triclosan for treating malaria.
- Based on an article by D. Balasubramanian
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Malaria: Glossary
Important terms used in connection with Malaria are given below.
The terms given do not necessarily appear in the present article.
Anopheles : A genus of mosquitoes in the family
Culicidae; members are vectors of malaria, dengue, and filariasis.
Anopheline : Pertaining to mosquitoes of the genus
Anopheles or a closely related genus.
Cinchona : The dried, alkaloid-containing bark
of trees of the genus Cinchona
Cinchonine : C19H22N2O. A colourless, crystalline
alkaloid that melts at about 245ºC; extracted from cinchona
bark, it is used as a substitute for quinine and as a spot reagent
for bismuth.
Cyst : A normal or pathologic sac with a distinct
wall, containing fluid or other material
Cytoplasm : The protoplasm of an animal or plant
cell external to the nucleus.
DDT : Common name for an insecticide; melting point
108.5ºC, insoluble in water, very soluble in ethanol and acetone,
colourless, and odorless; especially useful against agricultural
pests, flies, lice, and mosquitoes. Also known as dichlorodiphenyltrichloroethane.
Dengue : An acute viral disease of man characterized
by fever, rash, prostration, and lymphadenopathy; transmitted by
the mosquito Aedes aegypti. Also known as breakbone fever; dandy
fever.
Epidemiology : The study of the mass aspects of
disease.
Filaria : A parasitic filamentous nematode belonging
to the order Filaroidea.
Filariasis : A disease due to the presence of hairline
nematodes (filariae) in humans, including Wuchereria bancrofti,
W. pacifica, and Onchocerca volvulus.
Flagella : Relatively long, whiplike, centriole-based
locomotor organelles on some motile cells (sing. Flagellum).
Flagellate : 1. Having flagella. 2. An organism
that propels itself by means of flagella. 3. Resembling a flagellum.
Gamogony : Spore formation by multiple fission
in sporozoans. Sexual reproduction.
Inoculation : Introduction of a disease agent into
an animal or plant to produce a mild form of disease and render
the individual immune. Introduction of microorganisms onto or into
a culture medium.
Lymphadenopathy : Enlargement or disease of lymph-nodes.
Malaria : A group of human febrile diseases with
a chronic relapsing course caused by hemosporidian blood parasites
of the genus Plasmodium, transmitted by the bite of the Anopheles
mosquito.
Malaria pigment : Dark-brown, amorphous, micro-crystalline
and birefringent pigment found in parasitized erythrocytes, especially
with malarial parasites, and in littoral phagocytes of spleen, liver,
and bone marrow.
Merozoite : An ameboid trophozoite in some sporozoans
produced from a schizont by schizogony.
Motile : Capable of spontaneous movement.
Oocyst : The encysted zygote of some sporozoa.
Organelle : A specialized subcellular structure,
such as a mitochondrion, having a special function; a condensed
system showing a high degree of internal order and definite limits
of size and shape.
Parasite : An organism that lives in or on another
organism of different species from which it derives nutrients and
shelter.
Paroxysm : 1. A sudden attack, or the periodic
crisis in the progress of a disease. 2. A spasm, convulsion, or
seizure.
Pathogen : A disease-producing agent; usually refers
to living organisms.
Pigment : Any colouring matter in plant or animal
cells.
Plasmodium : A genus of protozoans in the family
Plasmodiidae in which all the true malarial parasites are placed.
Protozoa : A diverse phylum of eukaryotic microorganisms;
the structure varies from a simple uninucleate protoplast to colonial
forms, the body is either naked or covered by a test, locomotion
is by means of pseudopodia or cilia or flagella, there is a tendency
towards universal symmetry in floating species and radial symmetry
in sessile types, and nutrition may be phagotrophic or autotrophic
or saprozoic.
Quinidine : C20H24N2O2. A crystalline alkaloid
that melts at 171.5ºC and that may be derived from the bark
of cinchona; used as the salt in medicine. Also known as chinidine;
ß-quinine.
Quinine : C20H24N2O2. An alkaloid of cinchona,
used principally as an antimalarial drug.
Schizogony : A sexual reproduction by multiple
fission of a trophozoite; a characteristic of certain Sporozoa.
Schizont : A multinucleate cell in certain members
of the Sporozoa that is produced from a trophozoite in a cell of
the host, and that segments into merozoites.
Spore : A uni- or multicellular, asexual, reproductive
or resting body that is resistant to unfavourable environmental
conditions and produces a new vegetative individual when the environment
is favourable.
Sporogony : Reproduction of means of spores. Propagative
reproduction involving formation, by sexual processes, and subsequent
division of a zygote.
Sporozoa : A subphylum of parasitic Protozoa, typically
producing spores during the asexual stages of the life cycle.
Sporozoite : A motile, infective stage of certain
sporozoans, which is the result of sexual reproduction and which
gives rise to an asexual cycle in the new host.
Trophozoite : A vegetative protozoan; used especially
of a parasite.
Zygote : 1. An organism produced by the union of
two gametes.
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