Theiler, Max (1899-1972)

South African virologist

Max Theiler (pronounced Tyler) was a leading scientist in the development of the yellow-fever vaccine . His early research proved that yellow-fever virus could be transmitted to mice. He later extended this research to show that mice that were given serum from humans or animals that had been previously infected with yellow fever developed immunity to this disease. From this research, he developed two different vaccines in the 1930s, which were used to control this incurable tropical disease. For his work on the yellow-fever vaccine, Theiler was awarded the Nobel Prize in medicine or physiology in 1951.

Theiler was born on a farm near Pretoria, South Africa, on January 30, 1899, the youngest of four children of Emma (Jegge) and Sir Arnold Theiler, both of whom had emigrated from Switzerland. His father, director of South Africa's veterinary services, pushed him toward a career in medicine. In part to satisfy his father, he enrolled in a two-year premedical program at the University of Cape Town in 1916. In 1919, soon after the conclusion of World War I, he sailed for England, where he pursued further medical training at St. Thomas's Hospital Medical School and the London School of Hygiene and Tropical Medicine, two branches of theUniversity of London. Despite this rigorous training, Theiler never received the M.D. degree because the University of London refused to recognize his two years of training at the University of Cape Town.

Theiler was not enthralled with medicine and had not intended to become a general practitioner. He was frustrated by the ineffectiveness of most medical procedures and the lack of cures for serious illnesses. After finishing his medical training in 1922, the 23-year-old Theiler obtained a position as an assistant in the Department of Tropical Medicine at Harvard Medical School. His early research, highly influenced by the example and writings of American bacteriologist Hans Zinsser, focused on amoebic dysentery and rat-bite fever. From there, he developed an interest in the yellow-fever virus.

Yellow fever is a tropical viral disease that causes severe fever, slow pulse, bleeding in the stomach, jaundice, and the notorious symptom, "black vomit." The disease is fatal in 10–15% of cases, the cause of death being complete shutdown of the liver or kidneys. Most people recover completely, after a painful, extended illness, with complete immunity to reinfection. The first known outbreak of yellow fever devastated Mexico in 1648. The last major breakout in the continental United States claimed 435 lives in New Orleans in 1905. Despite the medical advances of the twentieth century, this tropical disease remains incurable. As early as the eighteenth century, mosquitoes were thought to have some relation to yellow fever. Cuban physician Carlos Finlay speculated that mosquitoes were the carriers of this disease in 1881, but his writings were largely ignored by the medical community. Roughly 20 years later, members of America's Yellow Fever Commission, led by Walter Reed, the famous U.S. Army surgeon, concluded that mosquitoes were the medium that spread the disease. In 1901, Reed's group, using humans as research subjects, discovered that yellow fever was caused by a blood-borne virus. Encouraged by these findings, the Rockefeller Foundation launched a world-wide program in 1916 designed to control and eventually eradicate yellow fever.

By the 1920s, yellow fever research shifted away from an all-out war on mosquitoes to attempts to find a vaccine to prevent the spread of the disease. In 1928, researchers discovered that the Rhesus monkey, unlike most other monkeys, could contract yellow fever and could be used for experimentation. Theiler's first big breakthrough was his discovery that mice could be used experimentally in place of the monkey and that they had several practical research advantages.

One unintended research discovery kept Theiler out of his lab and in bed for nearly a week. In the course of his experiments, he accidentally contracted yellow fever from one of his mice, which caused a slight fever and weakness. Theiler was much luckier than some other yellow-fever researchers. Many had succumbed to the disease in the course of their investigations. However, this small bout of yellow fever simply gave Theiler immunity to the disease. In effect, he was the first recipient of a yellow-fever vaccine.

In 1930, Theiler reported his findings on the effectiveness of using mice for yellow fever research in the respected journal Science. The initial response was overwhelmingly negative; the Harvard faculty, including Theiler's immediate supervisor, seemed particularly unimpressed. Undaunted, Theiler continued his work, moving from Harvard University, to the Rockefeller Foundation in New York City. Eventually, yellow-fever researchers began to see the logic behind Theiler's use of the mouse and followed his lead. His continued experiments made the mouse the research animal of choice. By passing the yellow-fever virus from mouse to mouse, he was able to shorten the incubation time and increase the virulence of the disease, which enabled research data to be generated more quickly and cheaply. He was now certain that an attenuated live vaccine, one weak enough to cause no harm yet strong enough to generate immunity, could be developed.

In 1931, Theiler developed the mouse-protection test, which involved mixing yellow-fever virus with human blood and injecting the mixture into a mouse. If the mouse survived, then the blood had obviously neutralized the virus, proving that the blood donor was immune to yellow fever (and had most likely developed an immunity by previously contracting the disease). This test was used to conduct the first worldwide survey of the distribution of yellow fever.

A colleague at the Rockefeller Foundation, Dr. Wilbur A. Sawyer, used Theiler's mouse strain, a combination of yellow fever virus and immune serum, to develop a human vaccine. Sawyer is often wrongly credited with inventing the first human yellow-fever vaccine. He simply transferred Theiler's work from the mouse to humans. Ten workers in the Rockefeller labs were inoculated with the mouse strain, with no apparent side effects. The mouse-virus strain was subsequently used by the French government to immunize French colonials in West Africa, a hot spot for yellow fever. This socalled "scratch" vaccine was a combination of infected mouse brain tissue and cowpox virus and could be quickly administered by scratching the vaccine into the skin. It was used throughout Africa for nearly 25 years and led to the near total eradication of yellow fever in the major African cities.

While encouraged with the new vaccine, Theiler considered the mouse strain inappropriate for human use. In some cases, the vaccine led to encephalitis in a few recipients and caused less severe side effects, such as headache or nausea, in many others. Theiler believed that a "killed" vaccine, which used a dead virus, wouldn't produce an immune effect, so he and his colleagues set out to find a milder live strain. He began working with the Asibi yellow-fever strain, a form of the virus so powerful that it killed monkeys instantly when injected under the skin. The Asibi strain thrived in a number of media, including chicken embryos. Theiler kept this virus alive for years in tissue cultures, passing it from embryo to embryo, and only occasionally testing the potency of the virus in a living animal. He continued making subcultures of the virus until he reached strain number 176. Then, he tested the strain on two monkeys. Both animals survived and seemed to have acquired a sufficient immunity to yellow fever. In March 1937, after testing this new vaccine on himself and others, Theiler announced that he had developed a new, safer, attenuated vaccine, which he called 17D strain. This new strain was much easier to produce, cheaper, and caused very mild side effects.

From 1940 to 1947, with the financial assistance of the Rockefeller Foundation, more than 28 million 17D-strain vaccines were produced, at a cost of approximately two cents per unit, and given away to people in tropical countries and the United States. The vaccine was so effective that the Rockefeller Foundation ended its yellow-fever program in 1949, safe in the knowledge that the disease had been effectively eradicated worldwide and that any subsequent outbreaks could be controlled with the new vaccine. Unfortunately, almost all yellow-fever research ended around this time and few people studied how to cure the disease. For people in tropical climates who live outside of the major urban centers, yellow fever is still a problem. A major outbreak in Ethiopia in 1960–1962 caused 30,000 deaths. The World Health Organization still uses Theiler's 17D vaccine and had mounted efforts to inoculate people in remote areas.

The success of the vaccine brought Theiler recognition both in the U.S. Over the next ten years, he received the Chalmer's Medal of the Royal Society of Tropical Medicine and Hygiene (1939), the Lasker Award of the American Public Health Association, and the Flattery Medal of Harvard University (1945).

In 1951, Theiler received the Nobel Prize in medicine or physiology "for his discoveries concerning yellow fever and how to combat it."

After developing the yellow-fever vaccine, Theiler turned his attention to other viruses , including some unusual and rare diseases, such as Bwamba fever and Rift Valley fever. His other, less exotic research focused on polio and led to his discovery of a polio-like infection in mice known as encephalomyelitis or Theiler's disease. In 1964, he retired from the Rockefeller Foundation, having achieved the rank of associate director for medical and natural sciences and director of the Virus Laboratories. In that same year, he accepted a position as professor of epidemiology and microbiology at Yale University in New Haven, Connecticut. He retired from Yale in 1967.

Theiler married in 1938 and had one daughter. Theiler died on August 11, 1972, at the age of 73.

See also Epidemics, viral; Epidemiology, tracking diseases with technology; History of immunology; History of public health; Immune stimulation, as a vaccine; Viruses and responses to viral infection; Zoonoses

Max Theiler

The South African-born American epidemiologist and microbiologist Max Theiler (1899-1972) received the 1951 Nobel Prize in physiology or medicine for developing a vaccine for yellow fever.

Max Theiler was born in Pretoria, South Africa, on January 30, 1899. His early schooling was in Pretoria and, because his father was Swiss, in Basel. Partly influenced by his father, who was a veterinary scientist, Max decided on a career in medicine, and in preparation he attended Rhodes University College in Grahamstown, South Africa, and the University of Capetown.

In 1911 Theiler enrolled at St. Thomas's Hospital, a well-known teaching hospital in London. In 1922 he was licensed to practice by London's Royal College of Physicians. The idea of medical practice, however, no longer appealed to him, and he enrolled in the London School of Tropical Medicine and Hygiene. Later that year he went to the United States, as he had been offered a position in the Department of Tropical Medicine at Harvard Medical School. While at Harvard he studied amebic dysentery and rat-bite fever, but his most far-reaching work was on yellow fever.

When Theiler began work on yellow fever, it was already known that a virus was responsible for the disease, that it was commonly transmitted by a mosquito, and that the disease could be controlled in populated areas by eradication of the breeding grounds of the mosquitoes. Still, an effective method of inoculation was necessary for full protection. One of Theiler's earliest contributions to the development of a yellow fever vaccine was the demonstration that laboratory white mice could be infected with the virus. When he introduced the yellow fever virus from a monkey into the brain of a white mouse and successively transferred the virus through several mice, he found that the virus underwent certain changes. It became progressively more serious in its effects on the mice, but at the same time its effects on monkeys lessened. These findings were the foundation of a mouse-derived vaccine.

In 1928 Theiler married Lillian Graham. Two years later he joined the Rockefeller Foundation in New York City to continue his work on yellow fever. The mouse-derived vaccine was being used cautiously on humans by some researchers, but Theiler felt it was not safe enough for general use. Within a few years he succeeded in developing a vaccine called 17D, derived from a chick embryo, which proved both safe and effective and is now widely used in human immunization against yellow fever. His discovery was announced in 1937 in the Journal of Experimental Medicine. After that his work was concerned with other insect-borne virus infections.

In 1950 Theiler became director of the virus laboratories of the Rockefeller Foundation and the following year director of the division of medicine and public health. In 1964 he was appointed professor of epidemiology and microbiology at Yale University.

Theiler retired from Yale in 1967. Although he immigrated to the United States in 1923, and remained there until his death on August 11, 1972 at the age of 72, he never applied for U.S. citizenship.

Further Reading

Theodore L. Sourkes, Nobel Prize Winners in Medicine and Physiology, 1902-1965 (1953; rev. ed. 1967), was a good introduction to Theiler and his work. See also Nobel Foundation, Physiology or Medicine: Nobel Lectures, Including Presentation Speeches and Laureates' Biographies, vol. 3 (1967). Some added insight was gained from Greer Williams, Virus Hunters (1959), and a detailed study of the entire yellow fever problem was in H. Harold Scott, A History of Tropical Medicine (2 vols., 1939). □

Max Theiler

1899-1972

South African-American microbiologist who was awarded the 1951 Nobel Prize for physiology or medicine for his research on yellow fever. Theiler's discovery that mice are susceptible to yellow fever expedited research on the disease and made possible the development of an attenuated strain of the virus. Theiler and his associates developed an improved vaccine that is widely used to protect humans against yellow fever. Theiler made many other contributions to tropical medicine and the study of infectious diseases.