ver since the beginning of history we have records of certain fevers that have been called by different names according to the people that were affected. As we study these names and the various writings concerning the fevers we find that a great group of the most important of them are what we to-day know as malarial fevers. Not only are these ills as old as history but they have been observed over almost the entire inhabited earth. There are certain regions in all countries where malaria does not occur, but almost always it will be found that other regions near by are infected and it very often happens that these infected regions are the most profitable parts of the land, the places where water is plentiful and vegetation is luxuriant. Indeed the coincidence of these two things, low-lying lands with an abundance of water, particularly standing water, and malaria has always been noted and gave rise to the earliest theories in regard to the cause of the disease.

For instance, we find some of the very early writers emphasizing the point that swampy localities should be avoided for they produce animals that give rise to disease, or that the air is poisoned by the breath of the swamp-inhabiting animals.

These views of the origin of the fever prevailed until about the beginning of the eighteenth century when the recently discovered microscope began to reveal the various kinds of animalculÆ to be found in decaying material.

In 1718 Lancisi held that the myriads of insects, particularly gnats or mosquitoes, that arose from such swampy regions might carry some of these poisonous substances and by means of their proboscis introduce them into the bodies of the people, and although he had made no experiments to test the assumption he did not consider it impossible that such insects might also introduce the smallest animalculÆ into the blood. It took almost two centuries of study and investigation before this guess was proved to be right.

One reason why the mosquitoes were not earlier associated with these diseases was that all who investigated the matter at all turned their attention to the bad condition of the air in these swampy regions. Malaria means bad air. We all know that we can see the mists arising from such regions, particularly in the evening or at night, and as exposure to these mists very often meant an attack of malaria they were naturally supposed to be the cause of the disease. So for a long time the whole attention of investigators was turned toward studying and analyzing these vapors, and various experiments were made which seemed to show conclusively that the malaria was caused only by these emanations. The investigations even went so far that the exact germs that were supposed to cause the fever were separated and experimented with.

THE PARASITE THAT CAUSES MALARIA

The blood had been studied time and again and the characteristic appearance of the blood of a malarial patient was well known. In 1880 Laveran, a French army surgeon in Algiers, began to study the blood of such patients microscopically and soon was able to demonstrate the parasite that caused the disease. His discoveries were not readily accepted, but other investigations soon confirmed his observations and the fact was gradually firmly established. Not until recently, however, did this distinguished physician receive a full recognition of his work. A few years ago he was awarded the Nobel prize for medicine, perhaps the highest honor that can be bestowed on any physician. It is interesting, too, to note in this connection that it was another French surgeon who in 1840 discovered that sulphate of quinine is a specific for malaria.

The next important step was made in 1885 by Golgi, an Italian, who studied the life-history of the parasite in the blood and distinguished the three forms which cause the three most familiar kinds of malarial fevers, the tertian, the quartan and the remittent types. From this time on this parasite has been studied by physicians of many nationalities and the whole course of its life-history worked out. In order that we may understand how it was that mosquitoes were determined to be the means of disseminating this parasite we will discuss first its life-history in the human blood.

The parasites that cause the malarial fevers are Sporozoans and belong to the genus Plasmodium. Other names such as HÆmamoeba and Laverania have been used for them, but the term Plasmodium is the one now most commonly employed. The three most common species are vivax, malariÆ and falciparum, causing respectively the tertian, quartan and remittent fevers.

LIFE-HISTORY OF PARASITE

The life-history of all of these is very similar, the principal difference being in the length of time it takes them to sporulate. Let us begin with the parasite after it has been introduced into the blood and trace its development there. At first it is slender and rod-like in shape. It has some power of movement in the blood-plasm. Very soon it attacks one of the red blood-corpuscles and gradually pierces its way through the wall and into the corpuscle substance (Fig. 99); here it becomes more amoeboid and continues to move about, feeding all the time on the corpuscle substance, gradually destroying the whole cell. As the parasite feeds and grows there is deposited within its body a blackish or brownish pigment known as melanin.

During the time that the parasite is feeding and growing it is also giving off waste products, as all living forms do in the process of metabolism, but as the parasite is completely inclosed in the corpuscle wall these waste products cannot escape until the wall bursts open. After about forty hours if the parasite is vivax or about sixty-five hours if it is malariÆ it becomes immobile, the nucleus divides again and again and the protoplasm collects around these nuclei, forming a number of small cells or spores, as they are called. In about forty-eight or seventy-two hours, depending on whether the parasite is vivax or malariÆ the wall of the corpuscle bursts and all these spores with the black pigment and the waste products that have been stored away within the cell are liberated into the blood-plasm.

These spores are round or somewhat amoeboid and are carried in the blood for a short time. Very soon, however, each one attacks a new red corpuscle and the process of feeding, growth and spore-formation continues, taking exactly the same time for development as in the first generation, so every forty-eight hours in the case of the vivax, and every seventy-two hours in the case of the malariÆ a new lot of these spores and the accompanying waste products are thrown out into the blood. Thus in a very short time many generations of this parasite occur and thousands or hundreds of thousands of the red-blood corpuscles are destroyed, leaving the patient weak and anemic. It will be seen, too, that the recurrence of the chills and fevers is simultaneous with the escaping of the parasites from the blood-corpuscles, together with the waste products of their metabolism.

These waste products are poisonous, and it is believed that this great amount of poison poured into the blood at one time causes the regular recurring crisis. ZoÖlogists well know that this process of asexual reproduction, i. e., reproduction without any conjugation of two different cells, cannot go on indefinitely, and those who were studying the life-cycle of these parasites were at a loss to know where the sexual stage took place. In the meantime studies of other parasites more or less closely related to Plasmodium showed that the sexual stage occurred outside the vertebrate host. The remarkable work of Dr. Smith on the life-history of the germ that causes the Texas fever of cattle had a strong influence in directing the search for this other stage of the malarial parasite. Another thing that indicated that this sexual generation must take place outside the body of the vertebrate host was the fact that the investigators found that the parasites in certain of the cells did not sporulate as did the others. When these individuals were drawn from the circulation and placed on a slide for study it was found that they would swell up and free themselves from the inclosing corpuscle and some of them would emit long filaments which would dart away among the corpuscles.

Many men have worked on this problem, but perhaps the most credit for its solution will always be given to Sir Patrick Manson, the foremost authority on tropical diseases, and to Ronald Ross, a surgeon in the English army. There is no more interesting and inspiring reading than that which deals with the development of the hypothesis by Manson and the persistent faith of Ross in the correctness of this theory, and his continuous indefatigable labors in trying to demonstrate it. It was an important piece of scientific work, and shows what a man can do even when the obstacles seem insurmountable.

THE PARASITE IN THE MOSQUITO

Briefly stated again, the problem was this: We have here a parasite in the blood which behaves as do many other forms of life. Some of these parasites do not go on with their development until they are removed from the circulation. Now, how are they thus removed from the circulation under normal conditions? This must first be solved before the still greater and more important problem of how the parasite gets from one human host to another can be taken up. In studying this over Manson reasoned that certain suctorial insects were the agencies through which blood was most commonly removed from the circulation and he ventured the guess that this change in the parasite that may be seen taking place on the slide under the microscope, normally takes place in the stomach of some insect that sucks man's blood. Ross was greatly impressed with the theory and began his long and apparently hopeless task of finding these parasites in the stomach of some insect. When we remember that they are so minute that they can only be seen by the use of the highest power of the microscope we can realize something of the magnitude of the task. Ross, who was at that time stationed in India, selected the mosquito as the most likely of the insects to be the host that he was looking for. For over two and one-half years he worked with entirely negative results, for after examining thoroughly many thousands of mosquitoes he found no trace of the parasite.

Practically all his work was done on the most common mosquito of the region, a species of Culex. But one day a friend sent him a different mosquito, one with spotted wings, and in examining it he was interested to note certain oval or round nodules on the outer walls of the stomach. On closer examinations he found that each of these nodules contained a few granules of the coal-black melanin of malarial fever. Further studies and experiments showed that these particular cells could always be found in the walls of the stomach of this particular species of mosquito a few days after it had bitten a malarial patient. This epoch-making discovery was made in 1898. Ross was detailed by the English government to devote his whole time to the further solution of the problem, and after two years more of careful experimentation and study was able to give a complete life-history of this parasite. His experiments have been repeated many times, and the conclusions he arrived at are as undeniable as any of the known facts of science.

The whole life-history as we now know it can be summed up as follows: The parasites develop within the circulation but certain of them seem to wander about and do not go on with their development there. When these particular parasites are taken into the stomach of most mosquitoes they are digested with the rest of the blood. But when they are taken into the stomach of a mosquito belonging to the genus Anopheles or other closely related genera they are not digested but go on with their development, conjugation and fertilization taking place, resulting in a more elongated form which makes its way through the walls of the stomach on the outside of which are formed the little nodules discovered by Ross on his mosquitoes. Within these nodules further division and development takes place until finally the nodule is burst open and many thousand minute rod-like organisms, sporozoites, are turned loose into the body-cavity of the mosquito. Owing to some unknown cause these little organisms are gathered together in the large vacuolated cells of the salivary glands of the mosquito, and when the mosquito bites a man or any other animal they pour down through the ducts with the secretion and are thus again introduced in the circulation.

The nodules or cysts on the walls of the stomach of the mosquito may contain as many as ten thousand sporozoites, and as many as five hundred cysts may occur on a single stomach.

It takes ten, twelve or more days from the time the parasites are taken into the stomach of the mosquito before they can go through their transformations and reach the salivary gland, the time depending on the temperature. So it is ten or twelve days or sometimes as much as eighteen or twenty days from the time an Anopheles bites a malarial patient before it is dangerous or can spread the disease. On the other hand, the sporozoites may lie in the salivary gland alive and virulent for several weeks. It does not give up all the parasites at one time, so that three or four or more people may be affected by a single mosquito.

It is well known that two parasites may often be seen in the same corpuscle. This is often simply a case of multiple infection, but Dr. Craig has very recently shown that under certain conditions two individuals may enter the same corpuscle and conjugate and the resulting individual will be resistant to quinine and may remain latent in the spleen or bone marrow for a long time. Under favorable conditions it may again begin the process of multiplication and the patient will suffer a relapse.

SUMMARY

Now let us sum up some of the reasons why we believe that the malaria fever can be transmitted only through the agency of mosquitoes. First, we know the life-history of the parasite, it has been studied in both of its hosts. Attempts have been made to rear it in other hosts but without avail, and we know from the general relations of the parasite that it must have this sexual as well as the asexual generations. Second, in some regions which would seem to be malarial, that is, where the miasmatic mists arise, no malaria occurs. Why? Usually it can be definitely shown that no Anopheles occur there. Other mosquitoes may be there in abundance, but if no Anopheles, there is no malaria. In certain regions this is well demonstrated. The west coast of Africa is one of the worst pest-holes of malaria and Anopheles. The east coast has no malaria and no Anopheles. In many islands the same condition exists. On the other hand, the Fiji Islands have Anopheles but no malaria. No malaria has ever been introduced there to infect the mosquitoes. In the same way Stegomyia occurs in some of the South Sea islands and yet there is no yellow fever there.

EXPERIMENTS

We may review, too, a few of the classic experiments that have served to show that malaria can be contracted in no other way than through the bite of the mosquito.

For many years Grassi, an Italian, devoted almost his whole time to the study of malaria. In 1900 he received permission from the government to experiment on the employees of a piece of railroad that was being built through a malarial region. This was divided for the purpose of the experiment into three sections, a protected zone in the middle and an unprotected zone at each end.

Those working in the protected zone had their houses completely screened and no one was allowed out of doors after sunset except they were protected with veils and gloves. Early in the season they were all given doses of quinine to prevent auto-infection. In the unprotected zone no screens were used and every one was allowed to go without special protection. The result for the summer was that there were no new cases of fever in the protected zone. In the unprotected zones practically all had the fever as usual.

In the same year two English physicians, Sambon and Low, went to Italy where they built a cabin in one of the marshes noted as being a malaria pest-hole. The house was thoroughly screened so that no mosquitoes could enter, but the windows were always open so as to admit the air freely day and night. Here they lived for three months, out of doors as much as they pleased during the day but inside where they were protected from the mosquitoes at night. No quinine was used and no fever developed, although all about them other people were having the fever as usual.

Another English physician who had not been in malarial regions allowed himself to be bitten by infected mosquitoes sent from a malarial locality. In due time he developed the fever. Many other experiments made in various places might be cited. The results have all been practically the same. To-day the soldiers of many civilized nations are required to protect themselves from mosquitoes because it has been found that it pays. Disease has always been a worse terror than bullets in any war, and we are fast learning that the great loss from diseases heretofore considered unavoidable may be very largely eliminated by proper sanitary arrangements and protection from noxious insects.