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Manson, Ross and Reed: pioneers in research on tropical diseases

Delivered 9th June 1936
By Sir Malcolm Watson, LL.D., M.D.. CM., D.P.H.. F.R.F.P.S. (Director of the Ross Institute of Tropical Hygiene, London School of Hygiene and Tropical Medicine.)

The opponents of research could not have seen the things that I have seen in the years during which I lived in the tropics; for if they had, I cannot believe they would still oppose experimental research. I have seen cholera sweep away thousands; I have seen men smitten so suddenly by cholera when walking along that they have dropped on the road in agony; and I have known fear of the disease drive hundreds in panic from their homes. I have seen a city so stricken by plague that to enter it was to run a grave risk. I have known whole families killed off by malaria, with only an aged and helpless relative left; mothers lose all their children; and once-prosperous provinces reduced to jungle by this disease.

As a direct result of the researches which some well-meaning but misinformed people would prohibit it has been my privilege to take a part in fighting and stamping out many dangerous diseases; so that in some places to a miserable people, half-starved, childless, barely clinging to life, there came health and prosperity and happy children.

So that the public may learn something of the truth about research and something of the great men who have devoted their lives to it, this lecture is delivered. In it I shall try to show how knowledge has come by research. Sometimes it has been acquired by dissecting insects or studying their habits; sometimes by infecting birds, mice and other animals with diseases from which both they and man suffer; sometimes by infecting man. At no time in the history of research has there been a lack of volunteers when men were required to risk or sacrifice their own lives and health for the benefit of their fellow creatures. When two young American soldiers, knowing full well the danger and suffering of an attack of yellow fever, allowed themselves to be bitten by infected mosquitoes, one of them said: “We are doing this solely in the interests of humanity and the cause of Science.” When both absolutely declined any monetary compensation, Major Walter Reed touched his cap, saying respectfully, “Gentlemen, I salute you." It is in a spirit of both humility and pride that we salute the memories of Manson, Ross and Reed. For are not their names written in burnished gold among those of the greatest benefactors of mankind?

Patrick Manson (1844-1922)
Elephantiasis
Filarial periodicity
The great experiment
Manson and malaria
Life or death?
Ronald Ross (1857-1932)
The malaria mosquito theory proved
Two dramatic experiments
The prevention of malaria
Walter Reed (1851-1902)
Yellow fever at Panama and Havana
The experiments at camp Lazear
A happy new year
The prevention of yellow fever
The triumph at Panama
Renewed research and discovery

PATRICK MANSON (1844—1922)

Patrick Manson, the first worker in the series of the researches of which I propose to speak to-day, was born in Aberdeenshire in 1844. His medical training was at Aberdeen University, where he passed through the usual medical course without any special training in scientific work. He records, in fact, how "terribly inadequate the medical training of these days" was ; but his desire, even at that time, to "search out" the cause of disease was revealed by his studies in the post-mortem room; and his first paper showed his remarkable aptitude for observing facts and enquiring into their causation and interpretation.

A year after graduating (1865) he went to Formosa, and five years later (1871) he settled in Amoy, a Chinese port some 60 miles north of the tropics. He had charge of a hospital for European seamen; among his unofficial activities was the medical charge of a missionary society's hospital and dispensary for Chinese. There were few Europeans resident in the place; the Chinese were miserably poor. One could hardly imagine a more uncongenial environment or a place with a more cramping influence on a young scientist. But if there were no laboratory facilities and no scientific societies to stimulate him to enter, and to assist him along the road of research, none were required. If the people were stricken by disease and poverty; if cholera swept the city from time to time "so that the dead and dying lay huddled together in the corners of the streets" and typhoid and other fevers made it their permanent abode; if, in fact, Manson lived dangerously, so far from disturbing his "aequanimitas," danger did but stimulate him to work. The spirit within led him to live laborious days and nights in the service of his patients. Manson saw that if progress were to be made in curing diseases he must first discover their causes, and happily he was one of those whom Stevenson described thus : "Study and experiment, to some rare natures, is the unbroken pastime of a life ; these are enviable natures . . . the common man cannot continue to exist upon such altitudes."

In this lecture it is impossible even to enumerate the original discoveries made by Manson in the course of his long and brilliant career. To-day, I must confine myself to his researches on filaria and malaria, and how these diseases were transmitted from one victim to another.

Elephantiasis

Figure 1. A case of elephantiasis with a moderate amount of swellingElephantiasis, a disease widely distributed throughout the tropical and sub-tropical world, causes anything from a mild inconvenience to intolerable misery and often death. The pictures which I show tell their own tale; but some pictures I have art too terrible to show except to a purely medical audience. Frequent attacks of inflammation lead to thickening of the skin and the underlying tissues, Fig. 1. The region attacked may be the head but frequently the lower limbs and the genital regions are affected. Of the cause of this terrible disease at that time nothing was known.  In Amoy, Manson found many sufferers from this disease. In his search for its cause his microscope showed a small worm in the blood of so many of his patients that he began to suspect there was some connection between these worms (embryos of Filaria bancrofti as we now call them) and elephantiasis disease, Fig. 2. But he asked, if there is a connection, why are the embryos not always found in the blood? To-day we know that the disease is only a frequent accident in the life history of the parasite. Manson did not know that then; but his researches on the worm were to lead to discoveries that can be called by no other word than epoch-making, and won for Manson the title of “Father of Modern Tropical Medicine.”

Filarial Periodicity

Figure 2. Filaria bancrofti embryo in its sheath, empty sheath, Filaria bancrofti embryo after escaping from its sheathIn the course of his researches Manson discovered that the worms disappeared from the finger blood of some patients during the day, to reappear in enormous numbers at night. He noticed, too, that when the blood was freshly drawn, each little worm was completely enclosed in a sheath, which hindered movements, as the sack hinders a runner in a sack race. When, however, the blood had been withdrawn from the human body and had lain cooling on the stage of the microscope for some time, the worm became much more active, pushed its way through the sheath, and seemed to be even more alive than it had been when first it had come from the body. This phenomenon, and that of the strange nightly periodicity, suggested to Manson's mind that the parasite escaped from the man to reach another man by means of a blood sucking insect, probably the mosquito, which is most active at night.

The Great Experiment

No sooner had idea occurred to Manson than he put it to the test. This was his experiment He fed a number of mosquitoes on a Chinese boy who had the worms in his blood, kept the mosquitoes for a few days and then dissected them. To his joy he discovered that, instead of being digested by the gastric juice of the insect's stomach, the little worms had bored their way into the tissues of the insect, and were actually growing. The strange changes in the growth of the worm that Manson saw left no doubt in his mind that the worm had found a congenial home in the insect, and that the insect was the means by which the worm was able  to pass from one host to another. Only in the last step of the process was Manson's genius to fail him ; and that only because the difficulty of keeping mosquitoes alive in captivity prevented him from observing the last stage of the worm's career in the insect, namely, its departure from the mosquito down its proboscis, by the way it had entered—a fact subsequently discovered in 1900 by Dr. George Carmichael Low, working on Filariasis at Manson's suggestion. Not having seen this, Manson concluded that the worm re-entered man when he drank water which had become infected with the worms when an infected mosquito died on the water.

In 1878, he published these discoveries in the Transactions of the Linncan Society; and so original were the conceptions that even 15 years later, when he propounded his mosquito malaria hypothesis in London men regarded him, to use a common term, as having “a bee in his bonnet.”

With this proof that the filaria and elephantiasis were transmitted by a mosquito, Manson had discovered the way to stop the spread of this disease; and in many parts of the world anti-mosquito work with this object must have saved many men and women from great misery and  suffering. But great as these benefits are to mankind, Manson's experimental work was to lead to other discoveries of incalculable benefits, of which I shall now speak.

After 25 years of medical and public work in China, Manson retired, but a year later (1890) started work in London. In 1892, he was appointed Physician to the Seamen's Hospital Society; in 1897, Mr. Joseph Chamberlain appointed him Medical Advisor to the Colonial Office an appointment that laid the foundations of the great School in which we are to-day and which has proved of the highest advantage to the Empire and the world.

Manson and Malaria

1. Young malaria parasite in a red blood cell. In 1894, Manson delivered the Gaulstonian lectures before the Royal College of Physicians on the “Life History of the Malaria Germ outside the Human Body.” He was interested in malaria for malaria kills more people every year than any other single disease. In his researches on the malaria parasite, he had been struck by one special form, the crescent body, which was in no way associated with the attacks of a fever which came with an almost clock-like regularity of either 24, 48 or 72 hours. The crescent body was apparently a spare piece in the jigsaw puzzle. Malaria is due to a parasite even more different from the filarial worm or its embryo than the proverbial chalk from cheese. The filarial worms wriggle about in the watery fluid of the blood. They are the children of highly organised male and female parents 2 to 8 inches long, which live, not in the blood vessels, but in the lymphatic vessels, and pour their offspring into the lymph fluid, and so into the blood stream. In contrast the malaria parasite, a microscopic speck of living jelly, one of the lowest forms of life, only one-fiftieth the size of the filarial embryo worm, lives within a blood cell sheltered at least for a period of its career from the police cells (white blood cells) which patrol the blood vessels and swallow intruders. Once in 24, 48 or 72 hours according to its species, it divides as lowly cells do, into many parts, each as complete as its parent. It can live months and even years in one 2. Full grown malaria parasite whose rupture produces an attack of fever.human host, reproducing itself by this vegetative process, Fig. 3. Attacks of "ague," "shivering" and “fever” are directly associated with these vegetative reproductions.

But although differing in so many ways, certain facts in the life history of the parasites suggested to Manson's mind that both might escape from their human hosts by being taken out of the blood and living for a period and developing in a blood-sucking insect. The nightly periodicity of the filaria embryo in the blood stream had suggested that this was an adaptation to that end, and his experiments had proved his induction to be correct. The fact that malaria is usually contracted at night, and in swampy places in which mosquitoes specially abound, suggested to Manson that the malaria parasite might escape in the same way as the filaria parasite. And he was confirmed in his idea by seeing in the blood stream a strange form of the malaria parasite (the crescent body) which became active only after the blood had been withdrawn from the body, just as the filaria worm became more active and threw off its sheath when it was under similar conditions. The crescent body was not associated with the attacks of “fever,” as the other forms of the parasite seen in the blood were.

3. New generation of fever-producing malaria parasites.  Figure 3 Asexual reproduction of the malaria parasite in man

Life or Death?

Most people regarded the crescent as having no significance and thought of the changes seen under the microscope as the agonies of a parasite in extremis. But Manson, with greater vision, regarded them as, and declared in his lectures that they were, the first stages in the parasite's life outside of man. Once again Manson's deduction was as brilliant as it was to prove beneficial. But living in London where there was no natural malaria, Manson saw no opportunity of putting his hypothesis to the crucial test— the experiment. Nevertheless, great ideas are immortal: inspiration to great achievement passes from one generation to another, and if Manson's opportunity for experiment were past, as it seemed, Fortune gave him Ross and linked the names of Manson and Ross for all time.

RONALD ROSS (1857—1932)

B.1 Male Crescent. C.1 Female Crescent. Male (B.2) and female (C.2) crescents change shape in the mosquito's stomach. Male crescent (B.3) throws off flagella, which fertilise the female crescent. Figure 4. Fertilisation of the female malaria parasite in the stomach of an anopheles mosquitoRonald Ross, whose father was a distinguished Army commander in India, was born in 1857, in view of the eternal Himalayan snows. An undistinguished student of medicine, he entered the Indian Medical Service in 1881. For some years, he carried out his army duties efficiently, but with no special interest in them. Then the poverty and distress, the misery, disease and deaths of the unhappy people of India stirred him to a deeper sense of his duty and opportunity. Malaria is the disease that causes more sickness, misery and death than any other single disease in India; and not only in India but throughout the tropics. About 1890, Ross began his study of the disease, but at first went astray for want of instruction. In 1804 he came to London, met Manson and was shown by Manson that malaria parasites were substantial things and not figments of the imagination.

Manson explained his idea of how mosquitoes carried malaria. He suggested that Ross should feed mosquitoes on patients in whose blood were the crescent bodies which, when seen under the microscope, produced and threw off the curious writhing threads called “flagella,” which some thought were merely death agonies, Fig. 4. In India Ross proceeded to do so. Early in his researches he noticed and reported to Manson the greater rapidity with which the “flagella” were produced in the juices of the mosquito's stomach than in blood on a slide drawn directly from the patient. He was unable, however, to find out what became of the “flagella.” They disappeared utterly. But with infinite patience he persevered. It was the patience of genius that takes no refusal. Not until two years later, not until he had dissected and searched through the bodies of hundreds of mosquitoes did he pick up the next clue. How easily it could have been overlooked, for it was but two or three clear cells, containing a few black grains lying in the stomach wall of a mosquito which had fed on a malarial patient. Happily he recognised them as the malaria parasites. He saw, in a special kind of mosquito with spotted wings which we now call an anopheles, Fig. 5. The clue led him in time to the end of the search.

Figure 5. Original sketch made by Sir Ronald Ross showing the position at rest of: (1) The anopheles mosquito which carries malaria, and (2) Culex and aedes mosquitoes which carry filaria and yellow fever.Ross was a poet as well as a scientist. In his great poem, “In Exile,” is the following well-known stanza, written on August 21st, 1897, the day after he had discovered the malarial parasite in the mosquito :—

This day relenting God,
Hath placed within my hand,
A wondrous thing; and God
Be praised. At His command
Seeking His secret deeds
With tears and toiling breath
I find thy cunning seeds,
O million-murdering Death.
1 know this little thing
A myriad men will save.
O Death, where is thy sting,
Thy victory, O Grave!

The malaria mosquito theory proved

Time does not permit me to speak of the difficulties which Ross had encountered in the course of his researches ; of his visiting and living in the most malarious places he could find; of his being struck down by severe malaria in one of these places ; nor of the difficulties which he surmounted, largely by the generous and ever available help of Manson, before he had finally and conclusively shown that the malaria parasite leaves man by being sucked up through the mosquito's proboscis when the mosquito feeds on man, and is injected into another man by the same route after an interval of some ten days. During the ten days in the mosquito the parasite is reproducing itself sexually; for the “flagellum” turned out to be the sperm from a male crescent which entered and fertilised a female crescent. This explained why the “flagellum” disappeared. After fertilisation the female crescent altered its shape, bored into the wall of the mosquito's stomach and reproduced many hundreds of young, which found their way to the mosquito's proboscis and so back to man. The later stages of this research were carried out by experiments on birds and with bird malaria. Fig. 6.

Two dramatic experiments

Figure 6. Laboratory at Calotta. Ronald Ross, Mrs Ross, Mahomed, a laboratory assistant and birds in cages 1898 To the world as a whole laboratory experiments have no meaning and make no appeal, so Manson devised two experiments which would teach the man in the street. One experiment consisted in sending two volunteers, the late Dr. Sambon and Dr. George Carmichael Low, to live in a mosquito-proof house at Ostia, one of the most deadly malarial places in the Roman Campagna, during the three most malarial months of the year.   There they lived like Italian peasants; but retiring each evening by the shelter of this mosquito-proofed house. Sheltered from mosquito bites they escaped malaria, while the unprotected peasants all round suffered severely.

The other experiment was even more dramatic and convincing. In it mosquitoes of the right species which had fed on patients suffering from malaria in Rome were sent to London and were allowed to bite two volunteers who had not been exposed to malaria previously (by having lived in the tropics). One volunteer was Manson's own son (Dr. Thorburn Manson; the other, Mr. Warren, of the London School of Tropical Medicine. After the usual incubation period both of the volunteers went down with malaria, and parasites of that disease were found in their blood. The mosquitoes fed in Rome had given these two people in London the Roman malaria. Nothing could be more convincing than these experiments and they left no doubt in any mind open to reason.

The prevention of malaria

Figure 7. A drain in central Africa cut to dry a swamp which Bred AnophelesMalaria had ceased to be a mysterious miasma or mist; its cause was known to be the parasite discovered by Laveran; the mode of infection was clear, thanks to the brilliant deduction of Patrick Manson and the genius and patience of Ronald Ross. And now for its prevention. It was characteristic of Ross's clear-seeing mind that from the very first, while appreciating the value of his discovery, he realised that “practical results” could not “be reasonably looked for” without further researches into the species of mosquito which actually carried the disease. He pointed out that : "We do not know all the dangerous species of mosquito, nor do we even possess an extensive knowledge of the haunts and habits of any one variety," and he advised "As each species is detected it will be possible to attempt measures at once for its extermination in given localities as an experiment."

As a direct result of the work of Manson and Ross and of later researches by others into the life habits of many species of mosquito, many methods have been devised for controlling and destroying the insects, with the remarkable result of reducing and in some places even completely eliminating malaria. Once again we had to return to experimental methods. But the experiments and work were no longer purely in the laboratory. They were more often in the field. Sometimes people with their houses were moved from one place to another; a careful record being made of the amount of malaria from which they suffered in the two places. Sometimes we felled jungle; sometimes we preserved it from being destroyed; sometimes we even planted swamps and valleys with trees; always recording results.


They were large scale experiments, sometimes extending over many years; but giving as clear and indisputable answers as experiments in test tubes. For as we learnt more about how mosquitoes lived, we saw that to prevent malaria  we must not follow one single method. A mosquito spends part of its life as a larva, wriggling about in water, just as the butterfly spends part of its life as a caterpillar. By altering the conditions under which the larvae of mosquitoes lived we could interfere with and often stop the propagation of the insect at this stage of its existence. Perhaps I can explain best what I mean by saying that if the larva of the dangerous species lived in deep shade, we could often drive it out by felling jungle and so removing the shade; if the larva loved a quiet life in a still pond, we created a current in the pond either by running a drain through it or by flushing it from time to time with a rush of water, Fig. 7; if the larva preferred sunshine and a clear, running stream, we shaded over the stream; or if the larva liked brackish water of a certain salinity, we increased or decreased the salinity so as to make the breeding place uncongenial for the insect. We learned how to say to species “Come” or “Go,” as we pleased. This work was begun in Malaya. Professor Swellengrebel carried these new ideas of how to control mosquitoe larvae and prevent malaria to Java and later to Europe, with brilliant success; Dr. Darling took them to the United States; Dr. Ramsay introduced them on a large scale with outstanding results into India. So one discovery leads to another, and the whole world benefits. Already we can claim to have saved a million lives and an incalculable amount of sickness and misery as a direct result of the researches of Manson and Ross on malaria alone; and we are only at the beginning of the practical application of these discoveries.

WALTER REED (1851—1902)

As a young surgeon in the United States' Army, Walter Reed spent many years in the outposts of Arizona and in the desert regions of the South-West. In the 'seventies and 'eighties of last century, communication in these areas was poor; long journeys had to be made by wagon over the roughest roads and among the most primitive conditions. Many of these journeys were not too "healthy" for the Apache Indian still resented the intrusion of the Pale Face. But Walter Reed was too keenly interested in improving his knowledge to be disturbed by the difficulties and dangers of his post; even in isolation he found opportunity; he missed no chance of improving his knowledge. As a result, in 1893 he was appointed Curator of the Army Medical Museum and Professor of Bacteriology at Washington. Because of his knowledge of Bacteriology and Hygiene, he was chosen by the Surgeon-General to investigate the cause of yellow fever when it attacked the United States Army of Occupation in Cuba, in 1899. It had caused 1,600 cases and 231 deaths.

Yellow fever was until the beginning of this century, one of the major scourges of Central America, the West Indies and the coast of America as far north as New York and as far south as Buenos Aires; and it was the one most greatly feared. For some 250 years, it had held undisputed sway in these parts of the world; sometimes seeming to disappear; at other times bursting out into an epidemic that caused a heavy mortality, particularly among the strangers in these lands. The old records from a medical point of view are, of course, in some respects incomplete, but they leave no doubt of the terror which the disease inspired. In 1649, the Island of Cuba was visited by the disease and 10,000 people out of a total population of 80,000 are recorded as having died of it. In 1741, of 12,000 troops who occupied Cartagena 8,481 died of it. In 1798 and again in 1802, yellow fever visited San Domingo, on the first occasion killing 22,000 troops and on the second occasion 20,000. The first epidemic of yellow fever on record in America was that in Yucatan in 1649. It lasted for two years. At first it attacked the Spaniards, but later among Indians "in many of their pueblos the same sickness showed as among the Spaniards, making fearful ravages as among a people without resources or medicine." There was fever and terrible pain "so violent that it appeared to dislocate them or to squeeze them as in a press." Delirium and the terrible black vomiting of putrified blood soon followed. Death came to end their sufferings in three or four days. "It attacked young men, the most robust and healthy with most violence and finished their lives the quickest. . . . Although very young women sickened the disease did not bear as hard on them as on men ... but it was rare that one found a pregnant woman who remained alive."

There are many reasons for believing that it was the disease chiefly responsible for the disappearance from the West Indies of that fine race, the Caribs.

Yellow Fever at Panama and Havana

When in 1885 the French attempted to build the Panama Canal, yellow fever, perhaps even more than malaria, frustrated the attempt. The record is terrible reading. The first French Director came to the Isthmus with his wife and two children; at the end of the first six months the others had died of yellow fever and he returned to France a broken man. A party of seventeen young French engineers went to the Isthmus; within a month all had died of yellow fever except one. The Superintendent of the Railroad brought his three sisters; within a month all had died of yellow fever. The Mother Superior of the Nursing Sisters in Ancon Hospital brought out 24 nurses with her; within a few years 21 had died, mostly of yellow fever. And so the dreadful tale was told, not merely from Panama but from all Central America and along the coast for more than a thousand miles north and south.

The cause of the disease was a complete mystery. It attacked the American troops when they were in Havana in 1898. At that time the disease was supposed to be due to filth. It was thought that if Havana were put in a state of proper cleanliness the disease might cease. The town was cleaned up, but the disease still continued; and not only continued but seemed to have a preference for the most highly paid and best housed in Havana. General Gorgas tells us that "It was the well-to-do class of Americans, and the highest officials on the staff of the Governor-General, who suffered out of all proportion to the rest of the population. In 1900, on the staff of the Governor-General, the chief quartermaster, the chief commissary, one of the aides, and one of the inspectors-general, all died of yellow fever, and the preceding year the chief quartermaster and the chief ordinance officer had died."  In 1898, there were 136 deaths; in 1899, 103; in 1900 no fewer than 810. "It looked very much as if the cleaner and better and more hygienic we got the City, the worse we were making yellow fever."

Although a Dr. Finlay had suggested that a mosquito might carry the disease as far back as 1881, he had not be able to prove it experimentally. But the experiments and discoveries of Manson and Ross were convincing and conclusive about filaria and malaria. Once again the idea born in China was reincarnated, if not in Peru, at least in Cuba, in Walter Reed, the head of the Yellow Fever Board appointed by the United States Government to inquire into the yellow itvtr attacking the troops in Havana. Yellow fever, like filaria and malaria, might be spread by the mosquito; and such a method of propagation would explain how in spite of improved sanitation the disease still continued to spread in Havana. The Board consisted of four medical men, Walter Reed, Jesse M. Lazear, James Carroll and Aristides Agramonte, each of whom pulled his weight in the team, although Reed was the chief and the master mind. During their preliminary investigations they heard of the observations of Dr. H. R. Carter, who pointed out that there was a delay between the primary and secondary cases of a yellow fever epidemic, which might well be explained by the disease developing in the mosquito in the same way that the filaria and the malaria parasites developed in that insect before they had reached a stage in which the insect could pass them on to the new host. Dr. Finlay's experiments had failed because he had not realised time was required for development of the infection in the mosquito before they could transmit the infection. He allowed his infected mosquitoes to bite healthy men too soon.

The Experiments in Camp Lazear

Nothing but experimental research could prove the truth or the falseness of the mosquito hypothesis or that of Carter in particular. No animal was known to suffer from the disease; no experiment was possible except on man. It was realised to the full that such experiments involved grave risk to the persons who were the subject of the experiments. So the members of the Board decided that it was their duty to run the risk themselves before submitting anyone else to it. That the risk was great was soon seen. Very early in the work of the Board Dr. Lazear died of yellow fever contracted from a mosquito which he deliberately watched biting him in a yellow fever ward. Then Dr. Carroll was deliberately infected, and suffered from a severe attack of yellow fever which damaged his heart and led to his early death.

The experiments were begun in 1900. A camp was built, isolated from every source of infection, and cleared of all mosquitoes. There were three series of experiments. In the first experiment, volunteers were put into the mosquito-proof hut. The hut was almost air-tight; there was scarcely any ventilation. The men slept on mattresses obtained from the yellow fever hospital in Havana on which yellow fever patients had died, mattresses soiled by their excreta and discharges, with sheets, pillows and pillow-cases stained with black vomit, and in pyjamas the patients had worn at the time of their death. For a period of 20 days they spent their nights in this building. As the volunteers, like most people, believed that yellow fever was spread by infected articles, they were very anxious for many days after the experiment began. Theirs was, indeed, bravery in cold-blood of the highest order. But all the men remained perfectly well. No case of yellow fever was contracted from exposure to these presumably highly infected articles. Clearly the infection was not carried by clothing.

In the second series of experiments a building was divided into two compartments by a partition of wire-netting, well ventilated and in good sanitary condition. In each compartment was a volunteer. They breathed the same air and had exactly the same surroundings, with the exception that they were separated by wire netting and that in one of the compartments were put mosquitoes (Aedes aegypti, as they are called to-day) which had fed on a case of yellow fever. The man in the compartment with the mosquitoes stayed on the first day for only 30 minutes in the forenoon and for 20 minutes in the afternoon; on the following day for 15 minutes. During these three short periods he was bitten by a total of fifteen mosquitoes. On the fourth day, the man went down with yellow fever. The man who had lived and slept in the other room, separated only by wire-netting, remained perfectly well. The experiments were repeated; with the same results. They proved that yellow fever is carried by a mosquito, just as filaria and malaria are carried by mosquitoes.

In the third series of experiments blood and filtered serum from patients with yellow fever was injected into a succession of healthy volunteers. The men developed yellow fever, and these experiments proved the disease was due to a living organism, although it could not be seen.

It is unnecessary here to speak in detail of all the experiments to ascertain how this very fatal disease is transmitted or the attempts to immunise men against it. In the course of the experiments several of the men had serious attacks of yellow fever; in a number life was in the  balance for several days; some unhappily died. In spite of this there was no lack of volunteers.

A Happy New Year

In a letter to his wife, dated 11.50 p.m., December 31st, 1900, from Columbia Barracks, Quemodos, Cuba, Walter Reed wrote: "Only ten minutes of the old century remain. ... It has been permitted to me and my assistants to lift the impenetrable veil that has surrounded the causation of this most wonderful, dreadful pest of humanity and to put it on a rational and scientific basis. I thank God this has been accomplished during the latter days of the old century. May its cure be wrought out in the early days of the new. The prayer that has been mine for 20 years, that I might be permitted in some way or at some time to do something to alleviate human suffering has been granted. A thousand Happy New Years. . . . Hark, there go the 24 buglers in concert, all sounding ' Taps ' for the .old year."

It was to be a happy New Year for many who would have died in that very New Year but for Reed's work. Reed himself lived to hear "Taps" at New Year only once more; but he had not lived in vain.

The Prevention of Yellow Fever

Now I must record, however briefly, the admirable way in which the Americans in that New Year applied the knowledge won; although even till to-day the cause of the disease has not been seen, for it is a virus that not even the strongest microscope can make visible. By exterminating the mosquitoes in the City of Havana, within a few months they had exterminated the disease. For the first time in 150 years the city was actually free from yellow fever. In the 10 years preceding the occupation of Havana by the Americans there had been an average of more than 480 deaths from yellow fever per annum. Anti-mosquito work was begun in February, 1901; in September of that year the last case of yellow fever occurred and, that was the end of yellow fever as an endemic disease in Havana.

Deaths from Yellow Fever in the city of Havana

 

18911892189318941895189618971898189919001901
Jan10151571510697187
Feb3106447241093
Mar414223302141
Apr5884614711200
May7723161027884020
Jun4113693116461743180
Jul66271187788116168162301
Aug6667100731202621021613492
Sep65706876135166563418522
Oct48544640102240422625740
Nov2452282335244261318540
Dec173311292014781322200
Total336357496382553128285813610331018

The Triumph at Panama

Then came the triumph at Panama. The French had failed because disease defeated them. The Americans triumphed because they first defeated disease. They built the Canal in record time. But they did more. They swept yellow fever completely out of the Canal areas, and this, in combination with their anti-malarial work, showed the world what could be done when the right men were in command. Had the death rate among the Americans been at the same rate as among the French, the completion of the canal would have cost 71,370 more human lives. That was not the whole saving. General Gorgas calculated that they also saved 39,420,000 days of sickness.

Renewed Research and Discovery

Following the triumphs at Havana and Panama, yellow fever was swept from its strongholds, the sea ports of North, Central and South America by the same measures that had cleared the disease from Havana and Panama. So successful was the work that it looked for a time as if yellow fever would entirely disappear from the face of the earth and become, in fact, merely of historic interest. But in 1926 a small outbreak which occurred in South America led to renewed research both in America and West Africa, research carried out largely by the staff and funds provided by the International Health Board of the Rockefeller Foundation. Once again the disease was to prove how deadly it could be; it claimed the lives of three distinguished workers in less than a year. Dr. Adrian Stokes died in September, 1927; Dr. Hideyo Noguchi and Dr. William Alexander both in May, 1928. One of the risks to those investigating the disease is that even the slightest contact with a drop of fresh blood from a patient or from an infected animal will infect through unbroken skin. By this time, however, Stokes, Bowyer and Hudson had discovered that an Indian monkey was susceptible to the disease. Subsequent researches by these workers and Theiler showed that mice could be infected with yellow fever; and they devised a test, using the brain of an infected mouse to determine whether the blood of a person contained evidence of his ever having had yellow fever or not. By these tests Sawyer, Lloyd, Mahaffy, Beeuwkes, Bauer, Soper and others have now proved that in extensive areas in South America, some of the jungle animals suffer and die from yellow fever; that in both South America and Central Africa some of the indigenous races of man suffer from a form of yellow fever which, although mild in them, is in many cases fatal to other races such as Europeans, Americans and Asiatics. These mild, human cases and the cases of yellow fever in the jungle animals form a reservoir of the disease, which is a formidable factor in the problem of its prevention.

Fortunately by infecting mice, a vaccine has been produced which now protects doctors and nurses attending patients suffering from this deadly disease; and it is also used to protect those whose duties take them into areas now known to have yellow fever either among men or animals.

All this experimental research has given us information which leads us to hope that we shall be able to prevent the spread of yellow fever into regions like Asia, at present free from the disease; but regions which, if the disease reached them, would on account of their dense populations be swept as if a fire had run through the prairies.

In this brief lecture, I have made no attempt to trace all the knowledge that has come from the idea which originated with Manson in China, and which inspired in succession Ross and Reed. Later it inspired others, and led to the discovery that plague, typhus fever, relapsing fever, sleeping sickness and other diseases are also spread by insects. I have not attempted to estimate the millions of lives that have been saved by these researches, or the countless millions of lives that have been made healthier and happier by them. Rather I would leave you with the thought of these three men, Manson, Ross and Reed, exiled in the heat and dust of far-off lands; with calm and steadfast minds amidst the terrors of cholera, yellow fever and other deadly plagues; often laughed at and sneered at; sometimes insulted and reviled; even obstructed, not only by the ignorant but by the "common man" in high places; resolute, tireless, unshaken; turning neither to the right hand nor to the left; doing the work to which they felt the Master had called them.


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