Lazear, Jesse William, 1866-1900

The U.S. Army Yellow Fever Commission (1900-1901) was a board of physicians that the U.S. government formed in order to determine how yellow fever was transmitted between hosts. Ultimately, the commission's experiments in Cuba proved that mosquitoes transmit yellow fever--a discovery that would spur successful campaigns to control and eradicate yellow fever throughout much of the globe.

When Major Walter Reed and Acting Assistant Surgeons James Carroll, Aristides Agramonte, and Jesse Lazear gathered on the porch of the Columbia Barracks Hospital in June of 1900, they became the fourth successive board of U.S. medical officers to grapple with the appalling plague that was yellow fever.

The persistence of this disease across the Cuban archipelago and its periodic re-emergence along the coastlines and great river drainages of the Americas was taking countless thousands of lives. Lack of precise knowledge as to its cause and transmission had augmented yellow fever's extraordinarily high mortality rate and had given rise to quarantine regulations which constituted substantial impediments to efficient regional trade. Endemic in the tropics, yellow fever imposed high humanitarian and economic costs upon the entire region. Specialists regarded Cuba as one of the principal foci of the disease, and the island consequently attracted considerable attention from the medical sciences.

In 1879, one year after a devastating epidemic swept up the Mississippi valley from New Orleans, Tulane University Professor Stanford E. Chaille led the first investigatory commission to Havana, Rio de Janeiro, and the West Indies. The Chaille Commission remained in Havana three months, and its members -- including George Miller Sternberg, who became Surgeon General of the Army, and Juan Guiteras, later Director of Public Health for Havana -- consulted with Cuban scientist Carlos J. Finlay. They concluded that the causal agent for yellow fever was possibly a living entity in the atmosphere, an assertion which set Finlay on the path to the mosquito theory he developed in 1881.

Louis Pasteur's foundational and highly successful work in modern immunology in 1880 and 1881 gave a renewed impetus to investigations aimed at discovering the "yellow fever germ." Over the middle years of the 1880s several scientists advanced different theories, all readily refuted by bacteriological work Sternberg undertook in Brazil and Mexico in 1887 and again in Havana in 1888 and 1889. In 1897, Italian scientist Giuseppe Sanarelli argued that Bacillus icteroides was the culprit, and the following year a third scientific team sailed to Cuba for additional tests. Eugene Wasdin and Henry D. Geddings appeared to confirm Sanarelli's assertion, though Sternberg, by then Surgeon General, remained skeptical.

Despite Wasdin and Geddings' insistence, the B. icteroides theory garnered significant opposition. In fact, a few months before the third commission's report reached the public, Walter Reed and James Carroll -- Reed's assistant at the Columbian University (later George Washington University) bacteriology laboratories in Washington, D.C. -- published a thorough refutation of the icteroides proposal: the bacteria was not a unique cause of yellow fever, but a variety of the hog cholera bacillus, "a secondary invader in yellow fever," Reed determined, unrelated to its etiology. [1] Dispute continued, however, and when Sternberg organized the fourth investigatory board, he charged Reed and his associates to settle the B. icteroides question once and for all, then to proceed with analysis of other blood cultures and intestinal flora from yellow fever cases.

Reed and Carroll had considerable experience in bacteriological analysis, and, Sternberg reasoned, might well be able to find the specific agent of the disease. Aristides Agramonte, a Cuban scientist who had worked in Reed's lab at the Columbian University in 1898, was also an accomplished bacteriologist; he had identified B. icteroides in tissue samples from cases other than yellow fever, providing further evidence opposed to Sanarelli's thesis. Jesse Lazear, a scientist from Johns Hopkins University in Baltimore, Maryland, had joined the Army Medical Corps to study tropical diseases at their point of origin; he received orders for Cuba in February 1900. Lazear impressed Reed with his abilities when the two men became acquainted in March. No doubt with Reed's advice, Sternberg assembled a crack team -- all experienced in scientific research, but each with interests as diverse as their temperaments. The mix of talent and personalities generated spectacular results.

What causes yellow fever? This simple, even obvious question had dictated yellow fever research for over two decades, and so it guided Reed in organizing the work of the commission. Bacillus icteroides and other bacteriological sampling dominated their work for the first months. "Reed and Carroll have been at that for a long time," Lazear wrote with some impatience to his wife on August 23, ". . . I would rather try to find the germ without bothering about Sanarelli." [2] Again and again, tests for the bacteria proved negative, and at the same time, perplexing cases of yellow fever were developing in the region. Agramonte and Reed investigated an epidemic at Pinar del Rio, 110 miles southwest of Havana; Lazear followed later to collect more specimens, and he also assessed the situation at Guanjay thirty miles southwest. To "my very great surprise," Reed admitted, the specific circumstances of the appearance and development of these cases gave strong evidence against the widely-accepted notion that the excreta of patients spread the disease. The theory of fomites -- infection from contaminated clothing and bedding -- and indeed even infection from airborne particles seemed altogether untrue. "At this stage of our investigation," Reed concluded, ". . . the time had arrived when the plan of our work should be radically changed." [3] The fundamental question underwent a subtle but critical transformation: from what causes yellow fever to what transmits it. A clear and accurate understanding of how the disease was spread would open a new avenue to its specific cause.

"Personally, I feel that only can experimentation on human beings serve to clear the field for further effective work," Reed stated to Surgeon General Sternberg, who concurred. [4] Evidence gathering around them pointed strongly to an intermediate host, and the Commission resolved to test Carlos Finlay's mosquito theory -- then not generally accepted -- on human volunteers. Nine times from August 11 to August 25, 1900, mosquitoes landed on the arms of volunteers and proceeded to feed. Nine times the results were negative. On August 27, Lazear placed a mosquito on the doubting Dr. Carroll, and four days later on William J. Dean, a soldier designated XY in the "Preliminary Note." [5] Both promptly developed yellow fever. Significantly, their mosquitoes had fed on cases within the initial three days of an attack and had been allowed to ripen for at least twelve days before the inoculations. Carroll vitiated the results of his experimental sickness by traveling off the post to Havana, a contaminated zone, even as Reed, ecstatic, wrote from Washington in a confidential letter: "Did the Mosquito do it?" [6] Dean's case seemed to prove it, since he claimed not to have left the garrison before becoming ill. Lazear also developed a case of yellow fever, almost certainly experimental in origin, though he never revealed the actual circumstances of his inoculation. His severe bout of fever took a fatal turn on September 25, 1900.

Nevertheless, these results could not have been more dramatic or convincing for the Commission. Reed quickly assembled a "Preliminary Note," which he presented to the annual meeting of the American Public Health Association in Indianapolis, Indiana, October 23, 1900. After initial consultations in Cuba with General Leonard Wood, military governor of the island, and with Surgeon General Sternberg in Washington, he returned to Cuba with authorization and funding to design and carry forward a fully defensible series of experiments. His aim was confirmation of the mosquito theory and invalidation of the long-held belief in fomites.

On open terrain beyond the precincts of Columbia Barracks -- the American military base just west of Havana near the adjacent suburban towns of Quemados and Marianao (also called Quemados de Marianao) -- Reed established the quarantined experimental station. Camp Lazear, as the Commission dedicated it, took form in the rolling fields of the Finca San Jose, on the farm of Dr. Ignacio Rojas, who leased the land to the Americans. Here Reed designed two small wood-frame buildings, each 14 by 20 feet, for the experimental work, and nearby raised a group of seven tents for the accommodation and support of the volunteers. The buildings faced each other across a small swale, about 80 yards apart, and stood 75 yards from the tent encampment. Building Number One, called the Infected Clothing Building, was a single room tightly constructed to contain as much foul air as possible. A small stove kept the temperature and humidity at tropical levels, and carefully attached screening secured the pair of doorways in a vestibule against intrusion by mosquitoes. Wooden blinds on two small sealed windows shielded the room from direct sun. Building Number Two, the Infected Mosquito Building, contained a principal room, divided into two sections by a floor-to-ceiling wire mesh screen. A door direct to the exterior let into one section, while a vestibule with a solid exterior door and pair of successive screened doors opened to the other, so configured to keep infected mosquitoes inside that section alone. The spare furnishings in both sections -- cots with bedding -- were steam sterilized. Windows exposed the entire room to the clean, steady ocean breezes and to sunlight. Like the doorways, they were carefully screened. A secondary room attached to the building but not communicating with the experimental spaces sheltered the small, heated laboratory where the Commission members raised and stored the mosquitoes to be used.

These two experimental buildings presented alternate environments -- one conspicuously clean and well ventilated, the other filthy and fetid. Contemporary theories of disease held that yellow fever developed in unclean conditions, and consequently much time and money had been devoted to sanitation projects. Workers steamed clothing, burned sulphur in ships' holds, and thoroughly scrubbed surfaces with disinfectant. In cases of severe epidemic, entire buildings presumed to be infected were set afire along with their contents. Thus the extraordinary -- and intentional -- paradox of the Commission's experimental regime: Reed expected yellow fever to develop not in the unsanitary environment, but in the one thought to be most healthful.

Camp Lazear went into quarantine the day of its completion, November 20, 1900, with a command of four immune and nine non-immune individuals, all save one U.S. Army personnel. Soon a group of recent Spanish immigrants to Cuba augmented the non-immune numbers, bringing the resident total to about twenty. Reed strictly controlled access to the camp and ordered regular temperature recording for each volunteer to eliminate any unanticipated source of infection and to identify the onset of any case of yellow fever as early as possible. As a result, non-immunes were barred from returning should they leave the precinct, and two of the Spaniards who developed intermittent fevers shortly after arrival were immediately transferred with their baggage to Columbia Barracks Hospital. The immune members of the detachment oversaw medical treatments and drove the teams of mules that pulled supply wagons and the ambulance. Experimentation did not begin until each volunteer had passed the incubation period for yellow fever in perfect health.

Reed took as much care with the design of the experimental protocol as he had with the configuration of the camp and its buildings. Each evening, the occupants of the infected clothing building unpacked trunks and boxes of bed linens and blankets, nightshirts and other clothing recently worn and soiled by cases from the wards of Columbia Barracks Hospital and Las Animas Hospital in Havana. These they shook out and spread around the room to permeate the atmosphere. The stench was overpowering. Yellow fever causes severe internal hemorrhaging, and its unfortunate victims often suffer from black vomit and other bloody discharges. One routine delivery proved so putrid the volunteers "retreated from the house," Reed stated. "They pluckily returned, however, within a short time, and spent the night as usual." [7] In two succeeding trials the protocol became progressively more daring, as the volunteers then wore the clothing and slept on the mattresses used by yellow fever patients, and finally put towels on their bedding smeared with blood drawn from cases in the early stages of an attack. Each morning, the volunteers carefully repacked the rank, encrusted materials into boxes and emerged to an adjacent tent where they spent the day quarantined from the rest of the company. Three trials of twenty days each involved seven men altogether, lead by Robert P. Cooke, a physician in the Army Medical Corps. None developed yellow fever.

The Commission's mosquito experiments proceeded in four series. First, Reed sought to demonstrate that mosquitoes of the variety Culex fasciata (later called Stegomyia fasciata, and later still Aedes aegypti ) could in fact transmit yellow fever, as Carlos J. Finlay had argued and the initial experiments at Camp Columbia strongly suggested. Here the Commission members simply applied infected mosquitoes contained in test tubes or jars to the skin of the initial volunteers. Success in these tests raised a number of questions, each one addressed in the subsequent series:

The second series consequently employed the specialized "Infected Mosquito Building" to indicate how a structure could be considered infected with yellow fever. This experiment required two groups of volunteers, one to be inoculated and another to serve as controls. "Loaded" mosquitoes, as the men called them, were released into the screened section of Building Two -- on the side with the protected vestibule entry. One or more non-immune men then entered the opposite section of the room through the direct exterior door, and lay down on bunks adjacent to the wire mesh screen in the center of the room. Now the young man to be inoculated walked through the vestibule into the mosquito side of the room and proceeded to lie on a bunk adjacent to the wire screen separating him from the controls. The inoculation volunteer remained in the building for about twenty minutes -- enough time to suffer several mosquito bites -- he then exited to a quarantine tent outside. The controls spent the remainder of the evening and night in the uninfected side of the room, and indeed returned to sleep in the room for as many as eighteen more nights. As Reed stated, absence of yellow fever in the controls showed "that the essential factor in the infection of a building with yellow fever is the presence therein of [infected] mosquitoes," and nothing more. [8] The degree of sanitation, so long considered critical, was utterly irrelevant.

The third series of mosquito experiments confirmed what Henry Rose Carter, of the U.S. Public Health Service, called the "period of extrinsic incubation," [9] the length of time required for secondary cases of yellow fever to develop after an initial intrusion of the disease into a locality. In this series, a single volunteer underwent three successive inoculations by the same mosquitoes, each group of inoculations interrupted by a period of time equal in length to the typical incubation period of the disease in humans, about five days. In this manner, the volunteer's illness could be specifically attributed to a single inoculation group. The use of the same mosquitoes and the same volunteer concurrently demonstrated that no peculiar personal immunity was at play, since logic dictates that a person susceptible to yellow fever on day 17 of a mosquito's contamination -- as happened in the experiment -- could not have been immune to yellow fever on day 11 or day 4. It was thus only the mosquito's capacity to infect which changed, and that occurred no less than 11 days after contamination.

The duration of time over which these "fully ripened" mosquitoes remained infective comprised the fourth series of experiments. For this series the Commission kept alive a group of infected mosquitoes for as long as possible, and proceeded to inoculate three volunteers -- on the 39th, 51st, and 57th day after contamination. Each developed yellow fever. A fourth volunteer declined to be bitten on day 65, and the last two mosquitoes of the group, "deprived of further opportunity to feed on human blood" [10] expired on day 69 and day 71, clear evidence that even a sparsely populated region may retain the potential for new infections more than two months after the first appearance of the disease.

Although it went unrecorded in the published papers, Reed organized a supplemental experiment to test another species of mosquito. Culex pungens failed to transmit yellow fever to at least one volunteer and probably to a second. Reed's preliminary conclusions indicated that Culex fasciata was the only species capable of transmitting yellow fever. [11]

A last experimental regime involved subcutaneous injections of blood from positive cases of yellow fever to presumed non-immunes. Reed devised these tests to confirm the presence of the yellow fever agent in the blood of a victim during the first days of an attack, and, more importantly, to settle the Bacillus icteroides question. The same blood cultures which produced yellow fever in four volunteers also failed to grow any B. icteroides, conclusively invalidating Sanarelli's claim.

Altogether, the mosquito inoculations and the blood injections produced fourteen cases of yellow fever. All made a full recovery.

Notwithstanding the decisive medical victory -- as Reed declared, "aside from the antitoxin of Diptheria and Koch's discovery of the tubercle bacillus, it will be regarded as the most important piece of work, scientifically, during the 19th century" [12] -- success at Camp Lazear unfolded in its own time. Initially, Reed observed, "the results obtained at this station were not encouraging." [13] The first inoculations of four volunteers over a period of two weeks proved disconcertingly negative each time. Then, on December 5, 1900, private John R. Kissinger presented his arm to the mosquitoes, and late in the evening on December 8, suffered the first chills of "a well-marked attack of yellow fever." [14] Three more men in rapid succession fell victim to the insects -- Spanish volunteers Antonio Benigno, Nicanor Fernandez, and Vicente Presedo. The force of the conclusions was evident to everyone:

"It can readily be imagined," Reed empathetically and wryly described in his first presentation of the experiments, "that the concurrence of 4 cases of yellow fever in our small command of 12 non-immunes within the space of 1 week, while giving rise to feelings of exultation in the hearts of the experimenters, in view of the vast importance attaching to these results, might inspire quite other sentiments in the bosoms of those who had previously consented to submit themselves to the mosquito's bite. In fact, several of our good-natured Spanish friends who had jokingly compared our mosquitoes to 'the little flies that buzzed harmlessly about their tables,' suddenly appeared to lose all interest in the progress of science, and, forgetting for the moment even their own personal aggrandizement, incontinently severed their connection with Camp Lazear. Personally, while lamenting to some extent their departure, I could not but feel that in placing themselves beyond our control they were exercising the soundest judgment."

"In striking contrast," Reed continued, the anxiety of the fomites volunteers began to melt into relief. "[T]he countenances of these men, which had before borne the serious aspect of those who were bravely facing an unseen foe, suddenly took on the glad expression of 'schoolboys let out for a holiday,' and from this time their contempt for 'fomites' could not find sufficient expression. Thus illustrating once more, gentlemen, the old adage that familiarity, even with fomites, may breed contempt." [15]

The question of human experimentation was indeed a serious one -- unavoidable, in actuality, as Reed had stated the previous summer to Surgeon General Sternberg. When the Commission first considered a trial of Finlay's mosquito theory, Reed, Carroll, and Lazear agreed to experiment on themselves. Agramonte, a native Cuban, had acquired immunity as a child. Doubtless Finlay's experience of many unsuccessful inoculations communicated that positive results would not be forthcoming rapidly, so before the first series of inoculations began under Lazear's direction at Columbia Barracks, Reed left Cuba for Washington, where he completed a monumental report on typhoid fever among the army corps -- left unfinished by the sudden death of co-author Edward O. Shakespeare. Carroll and Lazear both sickened while Reed was in Washington, and Lazear, young and strong, had no reason to anticipate that his case would be fatal. Reed was shocked at Lazear's death, and because of his own age -- 49, a decade and a half older than Lazear and a dozen years older than Carroll -- he resolved not to inoculate himself when he returned to Cuba on October 4, 1900. The point had already been amply demonstrated, and only a rigidly controlled experimental regime would establish the necessary proof. Carroll, however, remained embittered about this for the remainder of his life, though he evidently never communicated his objections directly to Reed.

That initial series of mosquito inoculations was probably accomplished without formal documentation of informed consent. Indeed, the experiments may also have been carried forward without the full knowledge of the commanding officer of Camp Columbia, and Reed consequently shielded the identity of Private William J. Dean, the second positive experimental case, behind the pseudonym "XY" in the "Preliminary Note." No such potentially troublesome problems arose for the experimental series at Camp Lazear; Reed obtained prior support from all of the appropriate authorities in the military and the administration, even including the Spanish Consul to Cuba. With the advice of the Commission and others, he drafted what is now one of the oldest series of extant informed consent documents. The surviving examples are in Spanish with English translations, and were signed by volunteers Antonio Benigno and Vicente Presedo, and a third with the mark of Nicanor Fernandez, who was illiterate.

The documents take the form of a contract between individual volunteers and the Commission, represented by Reed. At least 25 years old, each volunteer explicitly consented to participate, and balanced the certainty of contracting yellow fever in the general population against the risks of developing an experimental case, followed by expert and timely medical care. The volunteers agreed to remain at Camp Lazear for the duration of the experiments, and as a reward for participation would receive $100 "in American gold," with an additional hundred-dollar supplement for contracting yellow fever. These payments could be assigned to a survivor, and the volunteers agreed to forfeit any remuneration in cases of desertion.

For the American participants no consent documents appear to survive, though in contemporary letters Reed assured his correspondents that the Commission obtained written consent from all the volunteers. The record of expenses for Camp Lazear -- maintained by Reed's friend and colleague in the medical corps, Jefferson Randolph Kean -- indicates that the same schedule of payments for participation and sickness applied to the Americans as well. Volunteers who participated in the fomites tests and in addition the later series of blood injections and the single trial of an alternative species of mosquito also earned $100 each plus the $100 supplement if yellow fever developed. Two Americans declined these gratuities, as Kean termed them, Dr. Robert P. Cooke, of the fomites tests, and John J. Moran, who had recently received an honorable discharge from the service, and was the only American civilian to participate. His was the fourth case of yellow fever to develop from mosquito inoculation. Moran eventually settled in Cuba, where he managed the Havana offices of the Sun Oil Company, and late in life became a close friend of Philip S. Hench. Together the two men rediscovered the site of Camp Lazear in 1940 -- Building Number One still intact -- and successfully lobbied the Cuban government to memorialize there the work of Finlay and the American Commission in the conquest of yellow fever.

Reed informally commemorated his own experiences at Camp Lazear by commissioning a group photograph, evidently taken there shortly before he left Cuba in February 1901. A more important event occurred on the sixth of that month when Reed presented the results of the Camp Lazear yellow fever experiments to a great ovation at the Pan-American Medical Congress in Havana. Three days later he set sail for the United States, and once landed, drafted the Congress paper as The Etiology of Yellow Fever -- An Additional Note, published immediately in the Journal of the American Medical Association . [16]

Though his correspondence intimates a great appreciation for Cuba, Reed never returned to the warm, sunny shores of the island freed of a dreadful plague. Carroll stayed behind at Camp Lazear through February to complete the last experimental series officially bearing the imprimatur of the Yellow Fever Commission, and returned to Washington soon after March first. [17] The Medical Corps retained the lease on Camp Lazear against the possibility of continuing experiments another season, and Carroll, in fact, returned to Havana in August 1901 for a final experimental series, though he did not make use of Camp Lazear. This work involved at least three volunteers at Las Animas Hospital, Havana, who submitted to blood injections. Carroll's assignment aimed at a greater understanding of the yellow fever agent, and he proved that blood drawn from active cases of yellow fever remained virulent even after passing through fine bacteria filters. In addition, by heating contaminated blood which had previously caused cases of yellow fever, Carroll rendered it non-infective -- thereby establishing that this filterable entity, though sub-microscopic, was demonstrably present in the bloodstream. Carroll wrapped up the series in October and returned home to stay. [18] In Cuba, J. Randolph Kean made the last rental payments to Signore Rojas on October 9, 1901, and Camp Lazear, for more than a generation, slipped out of the realm of memory.

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Walter Reed (September 13, 1851 - November 22, 1902) was a U.S. Army physician who led the army's Yellow Fever Commission 1900 and 1901. Experiments conducted by the commission confirmed a theory that yellow fever is transmitted by mosquitoes--a discovery that led to the control and eradication of this disease across much of the globe. Reed would receive much of the credit for the work of the commission because of his role as its leader, and, long after his death in 1902, he would be widely celebrated as a heroic figure in the fields of public health and medical research.

Reed spent his first days in a small house which served as the parsonage for a Methodist congregation in Gloucester County, Virginia, where his father was minister.  Lemuel Sutton Reed and Pharaba White Reed welcomed young Walter into the family on September 13, 1851;  he was the youngest of their five children.  The Reeds moved to other Virginia parishes during Walter's childhood, and just after the close of the Civil War, transferred to the town of Charlottesville.  That move in 1866 placed Walter in the orbit of the University of Virginia, which he entered a year later at age sixteen under the care of his older brother Christopher, also a student at the University.  Reed attended two year-long sessions, the second devoted entirely to the medical curriculum, and he completed an M.D. degree on July 1, 1869, as one of the youngest students to graduate in the history of the medical school.

At that time the School of Medicine at the University offered little opportunity for direct clinical experience, so Reed subsequently enrolled at the Bellevue Hospital Medical College, in Manhattan, New York.  There he obtained a second M.D. degree in 1870.  Reed interned at a number of hospitals in the New York metropolitan area, including the Infants' Hospital on Randall's Island and the Brooklyn City Hospital.  In 1873, he assumed the position of assistant sanitary officer for the Brooklyn Board of Health.  The large and diverse population of New York, with its many immigrant communities and dense, tenement housing, provided countless medical cases to treat and study;  these served to expose Reed to the vital importance of public health, and developed in him a lifelong interest in the field.  Yet the frenetic life of the great cities began to pall after a few years: "Here the ever bustling day is crowded into the busy night; nor can we draw the line of separation between the two,"[1] he wrote to Emilie Lawrence, of Murfreesboro, North Carolina, later to become Mrs. Walter Reed.  Their courtship letters reveal much of his maturing character, interests, and philosophy of life.  Increasing responsibilities with the Board of Health precluded opening a private practice, and Reed's youth proved a barrier in a culture given to offering respect more to the appearance of maturity than to its actual demonstration. Reed consequently resolved to join the Army Medical Corps, both for the professional opportunities it offered immediately and for the modest financial security it could provide to a young man without independent means.  He passed the qualifying examinations in January 1875 and proceeded to his first assignment at the military base on Willet's Point, New York Harbor.

Reed remained in the Medical Corps for the rest of his life, spending many years of the '70s, '80s, and early '90s at difficult postings in the American West.  The first of these -- to the Arizona Territory -- began in the late spring of 1876, and indeed hurried along his wedding to Emilie Lawrence, on April 25, shortly before his departure.  She joined him the following November, and bore two children at frontier posts, a son Walter Lawrence and a daughter Emilie, called Blossom.

Reed's other western assignments included forts in Nebraska, Dakota Territory, and Minnesota, with two eastern interludes at Baltimore, Maryland and another at Mount Vernon Barracks, Alabama.  During the second of these tours in Baltimore -- over the 1890-1891 academic year -- Reed completed advanced coursework in pathology and bacteriology in the Johns Hopkins University Hospital Pathology Laboratory.  When he returned from his last western appointment in 1893, Reed joined the faculty of the Army Medical School in Washington, D.C., where he held the professorship of Bacteriology and Clinical Microscopy.  He also became curator of the Army Medical Museum and joined the faculty of the Columbian University in Washington (later the George Washington University).  In addition, Reed maintained close ties with professor William Welch and other leading lights in the scientific community he had come to know at Hopkins a few years earlier.

Beyond his teaching responsibilities for the Army and the Columbian University programs, Reed actively pursued medical research projects.  A bibliography of his publications finds entries from 1892 to the year of his untimely death a decade later, and the subjects he investigated range from erysipelas to cholera, typhoid, malaria, and yellow fever, among others.[2]   In 1896, a research trip to investigate an outbreak of smallpox took him to Key West, and there he developed a close friendship with Jefferson Randolph Kean, a fellow Virginian and colleague in the Medical Corps ten years his junior.  When Reed traveled to Cuba in 1899 to study typhoid in the army encampments of the U.S. forces, Kean was already there, and Kean was still in Cuba when Reed returned as the head of the Army board charged by Surgeon General George Miller Sternberg to examine tropical diseases including yellow fever.  Kean and his first wife Louise were great supporters of the U.S. Army Yellow Fever Commission's work, and Kean in fact served as quartermaster for the famous series of experiments at Camp Lazear.  After the dramatic and conclusive success of those experiments, Kean actively -- though unsuccessfully -- promoted Reed's candidacy for Surgeon General.

Reed continued to speak and publish on yellow fever after his return from Cuba in 1901, receiving honorary degrees from Harvard and the University of Michigan in recognition of his seminal work.  In November 1902, Reed developed what had been for him recurring gastro-intestinal trouble.  This time, however, his appendix ruptured, and surgery came too late to save him from the peritonitis which developed.  He died on November 23, 1902, almost two years to the day from the opening of Camp Lazear and the stunning experimental victory there.  Kean remained a champion of his deceased friend's role in the conquest of yellow fever.  He organized the Walter Reed Memorial Association, to provide support for Reed's family and to build a suitable memorial, and was instrumental in lobbying the United States Congress to establish the Yellow Fever Roll of Honor.  In 1929, Congress mandated the annual publication of the Roll in the Army Register, and struck a series Congressional Gold Medals saluting the Commission members and the young Americans who bravely suffered experimental yellow fever a generation before.

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Jesse William Lazear (May 2, 1866 - September 26, 1900) was a physician who was a member of the U.S. Army Yellow Fever Commission in 1900. Lazear's death from yellow fever at the outset of the commission's work in Cuba would lead to his elevation as a martyr for medical science in the eyes of many during the twentieth century.

"I rather think I am on the track of the real germ," Jesse W. Lazear wrote his wife from Cuba on September 8, 1900.[1] Seventeen days later, the fulminating case of yellow fever Lazear had contracted just over a week after writing Mabel H. Lazear suddenly ended the young scientist's life. He was 34 years old. Unlike so many other yellow fever fatalities, however, this one would lead to a direct and highly successful assault on the disease itself. Yellow fever's ascendancy, endemic in Cuba, was about to be undermined.

Lazear had reported to Camp Columbia, Cuba in February 1900 for duty as an acting assistant surgeon with the U. S. Army Corps stationed on the island. Here he undertook bacteriological study of tropical diseases, particularly malaria and yellow fever, and in May he was named to the Army board charged with "pursuing scientific investigations with reference to the infectious diseases prevalent on the island of Cuba."[2]

These orders placed him officially in the company of Walter Reed, James Carroll, and Aristides Agramonte -- the U.S. Army Yellow Fever Commission -- though Lazear had already met Reed the preceding March on a project to evaluate the efficacy of electrozone, a disinfectant made from seawater collected off the Cuban coast. While Reed was in Cuba that March, Lazear discussed with him the recent discovery of British scientist Sir Ronald Ross concerning the mosquito vector for malaria. At Johns Hopkins Hospital in Baltimore, where he was first a medical resident and later in charge of the clinical laboratory, Lazear had followed Ross's accomplishments with great interest, and pursued field work and experimentation on the Anopheles mosquito with fellow Hopkins scientist William S. Thayer. Lazear was thus the only member of the Commission who had experience with mosquito work, and was consequently the most open to the possible verity of Cuban scientist Carlos Juan Finlay's theory of mosquito transmission for yellow fever.

The record is apparently silent as to when Lazear first visited Finlay. Certainly by late June Lazear was beginning to grow mosquito larvae acquired from Finlay's laboratory, the first specimens brought to him by Henry Rose Carter, of the United States Public Health Service.[3] Not long after arriving in Cuba Lazear met Carter, whose own observations on yellow fever strongly suggested an intermediate host in the spread of the disease. However, Army Surgeon General George Miller Sternberg, who organized the Yellow Fever Commission, first charged the board members to investigate the relationship of Bacillus icteroides to yellow fever -- proposed by the Italian Scientist Giuseppe Sanarelli as the actual cause of the disease. "Dr. Reed had been in the old discussion over Sanarelli's bacillus and he still works on that subject," Lazear wrote his wife in July, "I am not all interested in it but want to do work which may lead to the discovery of the real organism."[4] Soon he would have the opportunity. The relatively quick failure of the Bacillus icteroides inquiry opened the door to what became the ground-breaking mosquito work, and Lazear was well placed to begin.

The project started in earnest on August 1, 1900. In a small pocket notebook Lazear noted the preparatory work of raising and infecting mosquitoes, and subsequently recorded the series of eleven experimental inoculations made from the 11th to the 31st of August, the last two producing cases of full-blown yellow fever. These two positive cases developed from mosquitoes allowed to ripen over a period of 12 days, and this was Lazear's crucial discovery. The epidemiological pattern was thus entirely consistent with Carter's observations of a delay between the primary and secondary outbreaks of yellow fever in an epidemic, and, in addition, explained why Finlay's experiments had been largely unsuccessful -- he had not waited long enough before inoculating his subjects.

Although Lazear never directly admitted to experimenting on himself, when Reed reviewed Lazear's sketchy notations he evidently found entries strongly suggesting Lazear's case was not accidental, as officially reported. Unfortunately, the little notebook so crucial to the preparation of the Commission's famous initial paper, The Etiology of Yellow Fever -- A Preliminary Note [5], vanished from Reed's Washington office after his own untimely death in 1902. Still, Lazear's invaluable contribution to the Commission's victory was widely recognized and elicited tributes from many quarters: "He was a splendid, brave fellow," Reed said of his young colleague, " and I lament his loss more than words can tell; but his death was not in vain- His name will live in the history of those who have benefited humanity." [6] "His death was a sacrifice to scientific research of the highest character," stated General Leonard Wood, military Governor of Cuba.[7] "Your husband was a martyr in the noblest of causes," Dr. L. O. Howard wrote to Mabel Lazear, "and I am proud to have known him. . . . His work contributed towards one of the greatest discoveries of the century, the results of which will be of invaluable benefit to mankind."[8] And so they were. Though Lazear's one-year-old son and newborn daughter never knew their father, they grew up in a world liberated -- almost in its entirety -- from the disease that killed him.

[1] Letter fragment from Jesse W. Lazear to Mabel Houston Lazear, 8 September 1900, Philip S. Hench Walter Reed Yellow Fever Collection, Claude Moore Health Sciences Library, Department of Historical Collections and Services, accession number: 00344001.

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Henry Rose Carter (August 25, 1852 - September 14, 1925) was a prominent physician in the U.S. Public Health Service who was a leading authority in the transmission and control of tropical diseases, particularly yellow fever and malaria. During his long career as a sanitarian, Carter undertook campaigns to investigate and control the spread of tropical diseases in Cuba, the Panama Canal Zone, the Southeastern United States, and Peru.

Like Walter Reed and Jefferson Randolph Kean, Henry Rose Carter was a native Virginian and a graduate of the University of Virginia. Carter obtained a civil engineering degree from Virginia in 1873 and also undertook post-graduate work in mathematics and applied chemistry the next year. Subsequently, however, Carter's interests turned towards medicine, and he completed a medical degree at the University of Maryland in 1879. The same year Assistant Surgeon Carter joined the Marine Hospital Service -- later the United States Public Health Service -- and the young surgeon rose steadily through the ranks, ultimately attaining the position of Assistant Surgeon General in 1915.

Carter's initial assignments with the Hospital Service placed him at the center of the yellow fever maelstrom. In 1879 he was detailed to Memphis and other Southern cities, then in the throes of a second year of devastating epidemics. Here began, as his colleague T. H. D. Griffitts observed, Carter's "lifelong interest in the epidemiology and control of yellow fever."[1] After several years of clinical practice in various Marine hospitals, Carter resumed a direct confrontation with yellow fever when his orders for duty with the Gulf Coast Maritime Quarantine assigned him to Ship Island, Mississippi, in 1888. Here and at subsequent quarantine station postings around the Gulf, he quietly championed a thorough review and rationalization of quarantine policies, with a view toward establishing uniform regulation, more thorough disinfection of vessels, and minimized interference with naval commerce. Crucial to the success of these activities was Carter's attention to the incubation period of yellow fever, which his on-site observations indicated to vary between 5 and 7 days. At the time the official literature stated with far less precision a variance of between 1 and 14 days; Carter's work consequently greatly increased the efficiency and effectiveness of quarantine operations.

Nevertheless, yellow fever continued to menace the temperate coastline of the United States, and Carter ably directed the Health Service's epidemiological control efforts in numerous threatened regions. In conjunction with this sanitary work for the 1898 season, Carter made detailed notes on the development of yellow fever at Orwood and Taylor, Mississippi. The isolation of these communities enabled him to identify more reliably the phenomenon of a delay between the initial cases of yellow fever in a locality and the subsequent appearance of secondary infection -- a delay two to four times longer than the incubation period of the disease in an infected person. Carter called this interval between the primary and secondary cases "the period of extrinsic incubation," and he defined its "usual limits . . . [as ranging] from ten to seventeen days."[2]

Before he was able to publish his conclusions, Carter took the helm of the quarantine service in war-time Cuba. There, in 1900, he met U. S. Army Yellow Fever Commission member Jesse Lazear. Carter had finally arranged for his paper's publication that year in the New Orleans Medical and Surgical Journal, and gave a draft to Lazear. "If these dates are correct," Carter later recalled Lazear saying, "it spells a living host."[3] The theory of mosquito transmission long advanced by Cuban scientist Carlos J. Finlay began to seem more likely. And indeed it was. The Commission's experiments in 1900-1901 irrefutably proved the mosquito vector and established the extrinsic incubation period at twelve days. Shortly after these successes Reed saluted Carter, "I know of no one more competent to pass judgment on all that pertains to the subject of yellow fever. You must not forget that your own work in Mississippi did more to impress me with the importance of an intermediate host than everything else put to-gether."[4]

Carter's long and distinguished sanitary career took him to the Panama Canal Zone in 1904, where he served as Chief Quarantine Officer and Chief of Hospitals for five years. He undertook detailed investigations and control measures of malaria in North Carolina and elsewhere in the South, and became a founder of the National Malaria Committee. With the support of the Rockefeller Foundation International Health Board, he undertook additional investigation and control measures for yellow fever in Central and South America. His expertise recommended him to the Peruvian government, which named Carter Sanitary Advisor in 1920-1921. Health problems at the end of his life compelled Carter to withdraw from active fieldwork, though he remained a highly valued consultant to the Health Board and a much-beloved and respected teacher for a new generation of sanitarians. Carter closed his career researching and writing the manuscript that his daughter Laura Armistead Carter edited and published posthumously in 1931: Yellow Fever: An Epidemiological and Historical Study of its Place of Origin. [5]

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Jefferson Randolph Kean (June 27, 1860 - September 4, 1950) was a U.S. Army physician who was a leading authority in sanitation, public health, and tropical diseases. Later in his career, Kean would become widely recognized for his role in organizing and administering medical services for the U.S. armed forces during World War I.

"He possessed one of the keenest, most scholarly minds I've ever encountered," recalled Nobel Prize winner Philip S. Hench of Jefferson Randolph Kean. [1] Kean and Hench shared an abiding interest in the work of the United States Army Yellow Fever Commission -- Kean, as a contemporary and supporter, and Hench, as a scholar and scientist intent on accurate historical documentation. On the advice of yellow fever experiment volunteer John J. Moran, Hench first wrote Kean in 1939. From that initial contact developed a close friendship which would last for the remainder of their lives. Kean entrusted Hench not only with numerous period documents, including original letters, accounts, fever charts, and other items, but also with the freely-given counsel and insight of a trusted friend.

Like Walter Reed and Henry Rose Carter before him, Jefferson Randolph Kean was an alumnus of the University of Virginia, completing the medical program there in 1883. Kean joined the U.S. Army Medical Corps in 1884, and after forty years in the service, retired with the rank of Colonel. Congress awarded him a promotion to Brigadier General, retired, in 1930. The early years of Kean's career passed in medical postings in the American West, and no doubt offered him experiences similar to those of Walter Reed, whom he met not on the frontier, but in Florida in 1896. Kean became an expert in tropical diseases and sanitation during his five-year assignment in the Florida tropics, an expertise which served him well over two terms of service later in Cuba. During the Spanish-American War and subsequent U. S. occupation of Cuba, Kean was Chief Surgeon for the Department of Havana, then Superintendent of the Department of Charities -- from 1898 to 1902. After a four-year interlude as an assistant to the Surgeon General in Washington, D.C., Kean again returned to Cuba as an advisor to the Department of Sanitation from 1906-1909.

Kean himself stated: "Reed and I were good friends before the Yellow Fever Board came to Cuba in June 1900, and [Reed] located himself at Marianao, 8 miles S. W. of Havana," to be within the medical and administrative jurisdiction overseen by Kean. [2] The Chief Surgeon did indeed offer significant assistance, and was an early convert to Carlos Finlay's mosquito theory of transmission, which the Yellow Fever Board's experiments ultimately proved true in the late autumn and winter of 1900-1901. As early as October 13, 1900 -- after the Board's preliminary work, but before the final convincing demonstrations -- Kean issued "Circular No. 8," concerning the latest scholarship on the mosquito vector for disease. [3] The circular contained a set of instructions for the entire command on mosquito eradication. Kean subsequently served as quartermaster and financial administrator for the famous series of yellow fever experiments at Camp Lazear and, for the rest of his life, Kean remained a strong proponent of the Commission's conclusions. He worked tirelessly not only to apply them in the field, but also to accord proper public recognition to the Commission's work.

In addition to his career as a sanitarian, Kean organized the department of military relief of the American Red Cross, and during World War One served as Chief of the U. S. Ambulance Service with the French Army and Deputy Chief Surgeon of the American forces. France named him an Officier de la Légion d'Honneur in recognition for these services. Cuban authorities as well offered Kean recognition with the grand cross of the Order of Merit Carlos J. Finlay, and he received both a Distinguished Service Medal from the United States government and the Gorgas Medal from the Association of Military Surgeons. For a decade after his retirement from active duty, Kean edited this last organization's medical journal, The Military Surgeon, and served on the Surgeon General's editorial board for the multi-volume history of the medical department in World War One. A great-grandson of Thomas Jefferson, Kean also took a seat with the government commission established to build the Jefferson Memorial in Washington, D.C. He held charter membership in the Walter Reed Memorial Association, and remained active in its affairs until his death in 1950.

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Philip Showalter Hench (February 28, 1896 - March 30, 1965) was a U.S. physician who in 1950 was awarded the Nobel Prize for Physiology and Medicine for his role in the discovery of the hormone cortisone. In addition to his medical research, Hench spent almost three decades of his life studying the history of the U.S. Army Yellow Fever Commission and became a leading authority in the subject.

Philip Showalter Hench was born in Pittsburgh, Pennsylvania, the son of Jacob Bixler Hench and Clara Showalter. After attending local schools, Hench entered Lafayette College and graduated from the school 1916 with a Bachelor of Arts. Hench completed his medical degree at the University of Pittsburgh in 1920, and subsequently entered a residency program at St. Francis Hospital, Pittsburgh. His association with the Mayo Clinic began in 1921 as a fellow at the institution. Two years later he would become an assistant at the clinic, and then, in 1926, he would be made the head of its Department of Rheumatic Diseases After pursuing post-graduate study in Germany in 1928-1929, Hench obtained a Masters of Science in Internal Medicine at the University of Minnesota in 1931, and a Doctor of Science degree from Lafayette College in 1940. Hench remained for the duration of his career at the Mayo Clinic, where his life-long passion for meticulous research and analysis brought him the Nobel Prize for Physiology and Medicine in 1950, which he shared with Edward C. Kendall and Tadeus Reichstein, for the discovery of cortisone.

The same persistence and determination present in his professional life is also evident in Hench's research on the U. S. Army Yellow Fever Commission's famous experiments. "As a physician particularly interested in medical history," he stated to experiment volunteer John J. Moran in 1937, "I have been long interested in the story of the yellow fever work in John J. Moran, Ralph C. Hutchison, Havana." [1] So began a remarkable odyssey. At the request of his friend Ralph Cooper Hutchison, then president of Washington and Jefferson College, Hench had written Moran to gather information for the dedication of the College's new chemistry building, named for Commission member and former Washington and Jefferson student Jesse W. Lazear. Hench also began a correspondence with another of the yellow fever experiment's original volunteers, John R. Kissinger. Moran's and Kissinger's recollections proved so intriguing that Hench initially offered to edit and publish them. However, in the course of his research Hench discovered that much general information on the topic was inaccurate. Conflicting assertions concerning the participants and unverified claims by medical and governmental authorities in the United States and Cuba -- often politically motivated -- clouded interpretation of the facts. "May I suggest," Moran consequently urged in 1938, "that a clearing up of the REED-FINLAY-CONQUEST-OF-YELLOW-FEVER, or an effort to do so, on your part, is a task far more pressing than publishing the Kissinger-Moran stories or memoirs." [2] Hench resolved to document every aspect of the "Conquest of Yellow-Fever" and to write a much needed accurate and comprehensive history.

For the next two decades, Hench tirelessly combed through public archive collections and personal papers in the United States and Cuba. He met and interviewed surviving participants of the experiments and others associated with the project, as well as family members of the Yellow Fever Commission. He sought out physicians and scientists who had worked with the principal players or who had applied the results in the campaign to eradicate yellow fever. He identified and photographed sites associated with the yellow fever story, and he successfully petitioned politicians in the United States and Cuba to commemorate the work. In the process, Hench became the trusted friend and advisor of many of these same individuals, and they, in turn, presented him with much of the surviving original material for safekeeping.

In short, Hench came to be the world's expert on the yellow fever story and the steward of thousands of original letters and documents. His premature death at age 69 found him still hoping to uncover important missing evidence, his book unwritten. Hench's widow Mary Kahler Hench gave his yellow fever collection to the University of Virginia, Walter Reed's alma mater, and this extensive personal archive forms the most detailed and accurate record available on the Conquest of Yellow Fever.

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From the guide to the Philip S. Hench Walter Reed Yellow Fever Collection, circa 1800-circa 1998, bulk 1863-1974, (Historical Collections, Claude Moore Health Sciences Library, University of Virginia)