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Research Lessons from Major Walter Reed By Walter Reed Army Hospital in Washington D.C. has a historic position in American medicine. President Eisenhower was hospitalized there, the room in which General Pershing died is a hallowed place, and the hospital was named for Major Walter Reed, the first researcher to formalize a covenant between medical investigators and human volunteers. Reed’s fame began when he found the cause of yellow fever by conducting simple staged, controlled experiments. Moreover, the successful results of that pioneering research were published quickly and soon benefited humanity. Before Reed’s discovery, yellow fever as an epidemic, usually fatal illness that produced immense suffering. Just between 1702 and 1878 in the USA, 112 epidemics of yellow fever were reported. Also, from 1793 to 1900, New Orleans reported 41,348 cases of yellow fever deaths, Memphis 7,759 and in both Charleston, South Carolina and Philadelphia more than 4,000. Louisville was not4e immune. Keating described the horrors of one of its epidemics: “Men, women, and children poured out of the city by every possible avenue of escape, by every possible conveyance, by anything that could float on the river, by trains which, especially from Louisville, were so packed as to make the trip to Cincinnati a positive torture for many delicate women every mile of the way. The stream of passengers seemed to be endless and they were as mad as they were many. The desire for personal safety broke through the social amenities. To the cities of the far North and West they fled, many of them to die on the way like dogs, neglected and shunned, as if cursed by God.” For centuries, yellow fever was oft4en believe to be “a visitation of God.” In 1793, Benjamin Rush maintained that it was produced by spontaneous generation along with filth, heat and moisture. In the 1800s, yellow fever often was attributed to unsanitary conditions that adequate sanitation would eliminate. The US Marine hospitals, such as the old one in Louisville, were the forerunners of the USPHS and provided what care they could for many victims. Typically, the disease, which was known as El Vomito Negro, went through four stages. The first (3 to 4 days) was characterized by fever, shivering, slow pulse, muscle pain, headache, nausea and diarrhea. The second, the stage of “Calm,” led many persons to think they were recovering, but it usually lasted for only about 24 hours. Then, the terrible third stage set in with its high fever, abdominal pain, jaundice, bleeding from the gastrointestinal tract and even the nose and mouth, and renal and hepatic failure followed by delirium and convulsions. The last, the fourth stage, was that of organ failure and death. The drama surrounding Major Walter Reed’s work and that of the Commission was heightened by the historical events of the 1890’s when the U.S.A. became an imperialistic nation. By the, the “Wild West” was settled; at the 1896 annual meeting of the American Historical Society, its President, Frederick Jackson Turner, delivered the famous “Passing of the Frontier” address. Also, the 1890s were marred by calamitous depressions, extensive unemployment, child labor abuses, and monopolies, all of which further stimulated territorial expansion. It was an era of “yellow journalism” in which Joseph Pulitzer and William Randolph Hearst played prominent roles. The well known “Wizard of Oz,” written at that time, satirized farmers as having no brains, the tin man without a heart as being a creature of the factory owners, and the lion as a politician inasmuch as our country was divided by bitterness between adherents of the free silver movement led by the populist, William Jennings Bryan, and those favoring the gold standard. In 1898, Hearst, who is often believed to have started the Spanish American War, sent the artist, Frederic Remington, the Havana to illustrate the ongoing political struggle between the Cuban Independents and the Spanish Government and the forthcoming war. Remington reported: “There is no trouble here. There will be no war. I wish to return.” Hearst replied: “Please remain. You furnish the pictures and I will furnish the war.” As we know, on February 15, 1898, the USS Maine exploded in Havana Harbor. A Spanish torpedo was blamed, and “Remember the Main, to Hell with Spain” became they cry for that “splendid little war.” The United States took over Puerto Rico, Cuba, and Guam, and paid $20,000,000 for the Philippine Islands. During the brief war, 968 military personnel were killed, but 5,000 died of disease, 85% from yellow fever. In 1900, the U.S. Army Surgeon General, George M. Sternberg, a bacteriologist who believed that bacteria “X” was the cause of yellow fever and that it could be controlled by proper hygiene, appointed the Reed Commission “for the purpose of pursuing scientific investigations with reference to the infectious diseases prevalent on the Island of Cuba.” It was headed by Major Walter Reed, a leading member of the U.S. Typhoid Board that, in 1898, established the importance of flies, human waste disposal, and healthy carrier states in the control of that disease. Reed had received one M.D. Degree from the University of Virginia in 1869 and another from Bellevue Hospital in 1871. He joined the Army Medical Corps in 1875 and was a frontier surgeon in 14 locations during the next 17 years. In 1892, he became professor of clinical and sanitary microscopy at the Army Medical School and also worked under Welch and Osler at Johns Hopkins. Reed’s methods in Cuba in 1899 were to: 1) research the problem; 2) recruit the team; 3) administer the research; 4) construct simple, ethical, exact experiments; 5) use open-minded analytical processes; 6) present honest, timely reports; 7) reevaluate the problem; and 8) conduct further research. The other members of the famous Commission were:
1) James Carroll, who was born in England, worked as an immigrant
lumberjack in
2) Jesse Lazear, age 34, had obtained his M.D. degree
from Columbia University,
3) Aristides Agramonte, born in Cuba in 1868, was immune to
yellow fever. He had
In June-July 1900, the Reed Commission set up research facilities in Cuba that included special rooms and buildings; for example, some were screened, one was the “infected clothing” building, etc. The Commission moved quickly. In July, they obtained blood on 18 patients and did 11 autopsies but could not find an organism and thus disproved theories of a bacterial cause. On August 2, 1900, the members of the Commission and 8 (later more) volunteers took a decisive step by agreeing to become research subjects. First, Lazear and 8 volunteers were bitten by a research mosquito known not to be infectious; none developed yellow fever. Then, on August 17, Carroll was bitten by a “loaded” mosquito and developed yellow fever as did volunteer Dean, who was bitten by Carroll’s mosquito and then isolated. On September 12, Lazear was bitten again, developed yellow fever September 18, and died in 7 days. In September, Reed gave a preliminary research report in Washington and returned to Cuba where he identified some of the research problems. Specifically, Carroll, who had developed the disease, had not been isolated after being bitten, and Dean, who had been isolated, also developed yellow fever. It was not known for certain whether Lazear had been accidentally inoculated, begun an auto-experiment, or was accidentally bitten by a random loaded mosquito. In October 1900, Reed went to Washington to deliver: “The Etiology of Yellow Fever: A Preliminary Note,” at the American Public Health Association meting. IN Cuba, Camp Lazear was opened November 20 and, in December, fomite studies and infectious mosquito studies began. The incubation period was established. Jose Martinez was bitten by the same loaded mosquito on incubation days 1, 4, and 11, but did not become ill until four days after bitten on the 17th day. Private John Kissinger spent 10 days in isolations, was bitten by the same loaded mosquito on days 17 and 22, then contracted yellow fever. Private Warren Jernigan lived in the “infected clothing” building 20 days and did not become ill. Then, he was bitten by a loaded mosquito on its 13th incubation day and did not become ill. But, after being injected with 2 cc of an infected patient’s blood, he developed yellow fever in three days. That same experiment was repeated in three additional volunteers, all of whom contracted yellow fever. In January 1901, more serum studies and incubation period studies were completed, and in February, Reed spoke on the “Etiology of Yellow Fever: An Additional Note” at the Pan-American Medical Conference in Havana. He and Carroll then went to the U.S.A. Carroll returned to Cuba in August 1901 to carry out further incubation period studies. In an important study, volunteer 1 was bitten by a loaded mosquito and his infected blood collected, filtered and injected into volunteer 2 who developed yellow fever. But, when the blood was both filtered and heated before being injected into volunteer 3, he did not become ill. Thus, it could be concluded that the causative agent of yellow fever was a submicroscopic, filterable organism that was killed by heat. The exciting, heroic research of the Reed Commission was aided by such other investigators as Carlos Juan Finlay, the “mosquito man.” He had graduated from Jefferson Medical College in 1855, practiced in Cuba for many years, and conducted over 104 unsuccessful experiments with aedes egypti in migrant workers in efforts to prove that an organism he named Bacterium icteroides was responsible for yellow fever. Also, brave Spanish volunteers allowed themselves to be bitten in studies of the life of the mosquito and of the incubation period. On December 31, 1901, Reed presented “The Etiology of Yellow Fever: An Additional Note” to the Society of American Bacteriologists in Chicago. Unfortunately, his life had a tragic ending. He died that next year, at age 52, in 1902 of appendicitis complications. Fortunately, he is memorialized by having our most famous military hospital named for him. In 1935, the Nobel Prize was given to XX for developing a yellow fever vaccine (JJS – don’t forget Wood and Gorgas in Cuba in 1901 and 1902, control of yellow fever, and the Commission’s achievements, including informed CONSENT) (typist’s note: Max Theiler received the Nobel Prize in 1951 for his work with yellow fever vaccines – cannot find any reference on Nobel Prize website for anyone receiving one in the 30’s for such a thing – you might want to drop that sentence?) The Reed Commission found that only female mosquitoes transmitted the diseases and that it began about three days after the second bite. In 1900, the Commission confirmed that Aedeas egyptis was the vector and, in 1901, determined that a Flavavirus was the agent that produced the disease, along with filth, heat, and moisture. Transmission is horizontal, for example, between humans and monkeys and also vertical, from mosquito to its eggs back to the mosquito. The insect is contagious for all 62 days of its life and its eggs are also infected. Inasmuch as the virus incubates for 17 days in the mosquito, the second bite produces the is infectious in humans. Those who recover are immune for life. Major General Leonard Wood, who later became the Governor of Cuba, issued the famous General Order #6 for mosquito control in Cuba December 21, 1900. The era was a favorable one for medical research, especially on the infectious diseases. The work of Louis Pasteur and that of Robert Koch late in the century followed the great advances in sanitation and public health, the cellular pathology of Rudolph Virchow, and identification of the causative agents of cholera, tetanus, diphtheria, typhoid and many other diseases. In 1898, Ginseppe Sanarelli reported in the Annals of the Pasteur Institute that he had analyzed blood cultures of yellow fever patients, experimentally injected culture specimens into well patients without their consents and had isolated the organism responsible for yellow fever and named it Bacillus icteroides.
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