Exposed: Scientists Who Risked Disease for Discovery

views updated

Exposed: Scientists Who Risked Disease for Discovery

Introduction

Most physicians would not find much commonality between yellow fever and stomach ulcers. Yellow fever is a viral illness spread by the bite of an infected mosquito, and spiral-shaped bacteria living in the extremely acidic environment of the stomach cause the majority of stomach ulcers. The common thread lies in the stories of the medical researchers who solved the mysteries presented by these otherwise distinct ailments.

History and Scientific Foundations

Yellow fever is a viral disease now preventable by vaccination, but until the early twentieth century, this virus caused epidemics of severe disease and death. Called “yellow jack,” yellow fever caused yearly summer epidemics in American coastal cities, and the disease struck year round in the tropics. The initial attempt by French engineers to build the Panama Canal in the 1880s failed in large part due to yellow fever and malaria putting a majority of canal workers in either the hospital or the grave. The United States Army lost more troops to yellow fever during the Spanish American War than to any other single cause. Some regiments lost over 50% of their men to yellow fever. When the United States began to plan resuming construction of the canal in the 1890s, medical officials realized the need to deal with yellow fever.

In 1900, United States Army Surgeon General George Sternberg (1838–1915) appointed four United States Army physicians to serve on the fourth Yellow Fever Commission. The physicians—Walter Reed (1851–1902), James Carroll (1854–1907), Aristides Agramonte (1868–1931), and Jesse Lazear (1866– 1900)—received orders to travel to Cuba and initiate experiments to discover the cause of yellow fever. The prevailing medical wisdom asserted that yellow fever infected people when they came in contact with clothing or bedding contaminated by those afflicted with yellow fever. A competing theory taught that the bite of infected mosquitoes spread yellow fever. In 1897, physicians Ronald Ross and Patrick Manson showed that the Anopheles mosquito carried malaria, and Carlos Finley, a Cuban physician, had long-championed the belief that yellow fever was also carried by a mosquito.

The four physicians of the Yellow Fever Commission quickly found evidence refuting the contaminated bedding theory, but they soon discovered providing evidence for the mosquito transmission theory would require dramatic actions. Yellow fever affected only humans. Animals are not susceptible. In order to show the bite of infected mosquitoes caused yellow fever, human volunteers needed to allow themselves to be bitten. The physicians agreed to experiment on themselves before requesting human volunteers. Agramonte was immune to yellow fever since he had acquired the disease years earlier, and Reed traveled back to Washington to complete a report to Surgeon General Sternberg. As the only physicians available, Lazear and Carroll, began the experiments with humans.

The doctors obtained mosquitoes that had fed on those suffering from yellow fever, and in late August 1900, James Carroll allowed these mosquitoes to feast on his blood. He fell sick a few days later. Two days later a second human volunteer, Private William Dean of the Seventh Calvary, also contracted yellow fever after a deliberate exposure to infected mosquitoes. Both Carroll and Dean recovered; however, Carroll's co-worker, the physician Jesse Lezear, developed a fatal case of yellow fever. Lezear's exposure was officially ruled accidental, but many historians argue Lezear also allowed himself to be a human guinea pig. The determination of accidental exposure allowed life insurance payments to his family. Reed, Carroll, and Agramonte went on to carry out a series of experiments, which conclusively showed the mosquito, Aedes aegypti, transmitted yellow fever.

The research did not provide the cause of yellow fever. Many years would pass before research determined yellow fever to be due to a virus, but showing that mosquitoes spread the disease provided a means to control yellow fever. American public health physicians rapidly declared war on the mosquito populations in American cities, and the summer epidemics of yellow fever along the southern and gulf coasts soon became a memory. The building of the Panama Canal in the early twentieth century proceeded without the horrific death toll of malaria and yellow fever due to aggressive control of the mosquito population.

Fast-forwarding nearly a century, stomach ulcers presented a serious problem as these ulcers frequently caused life-threatening bleeding. Stomach ulcers could be treated, but not cured. Few physicians investigated stomach ulcers since the cause of these ulcers was not in dispute; most physicians assumed and taught that stress together with dietary indiscretion caused stomach ulcers. Excessive acid in the stomach due to stress, diet, or smoking corroded the stomach lining and produced an ulcer.

Treating patients with acid-lowering drugs seemed to confirm this thinking as the ulcers did respond to the treatment; however, when patients stopped the drugs, the ulcers recurred. Pathologist J. Robin Warren (1937–) found odd bacteria present in the stomachs of many patients with stomach ulcers and gastritis (inflammation of the stomach lining). These bacteria presented a difficulty to explain because conventional medical wisdom thought bacteria could not survive in the highly acidic environment of the stomach. Another Australian physician, Barry Marshall (1951–), became interested in these novel bacteria, which eventually received the name Helicobacter pylori.

Marshall, collaborating with Warren, began to collect evidence that the spiral-shaped bacteria caused stomach ulcers. Since medical establishment already “knew” the cause of ulcers, Marshall's ideas resulted in considerable skepticism. The medical community derided Marshall's ideas and provided him little funding for research. Despite the obstacles from 1981 to 1984, Barry Marshall gathered considerable evidence implicating H. pylori as a cause of stomach ulcers and gastritis. The bacteria were present in biopsy specimens taken from ulcer patients, and grown in pure culture from these specimens. However, like the case with yellow fever, no animal model existed to study stomach ulcers. Marshall could not inoculate an ulcer-free animal with the H. pylori bacteria and show that ulcers or gastritis developed. This experiment was essential to show that H. pylori did indeed cause stomach ulcers, and the bacteria were not just colonizing (maintaining a population without causing disease) in the human stomach.

WORDS TO KNOW

BIOSAFETY LABORATORY: A place for scientific study of infectious agents. A biosafety laboratory is specially equipped to contain infectious agents, prevent their dissemination, and protect researchers from exposure.

COLONIZATION: Colonization is the process of occupation and increase in number of microorganisms at a specific site.

HELSINKI DECLARATION: A set of ethical principles governing medical and scientific experimentation on human subjects; it was drafted by the World Medical Association and originally adopted in 1964.

INFORMED CONSENT: An ethical and informational process in which a person learns about a procedure or clinical trial, including potential risks or benefits, before deciding to voluntarily participate in a study or undergo a particular procedure.

By 1984, Marshall and Warren had a good circumstantial case implicating H. pylori as the causative agent of most stomach ulcers. They also developed a treatment strategy, which clearly both destroyed the bacteria in the stomach and healed the ulcers and gastritis. What they still lacked was definitive proof that when H. pylori infected someone, ulcers or gastritis developed. Marshall knew he would not likely be able to get permission to experiment on humans, so he decided to swallow a pure culture of H. pylori. He would be the animal model to see if ulcers developed. He had already determined that his stomach did not harbor H. pylori. Within a week of ingesting the bacteria, Barry Marshall had classic symptoms of gastritis. Biopsies from his stomach showed bacteria and infection where previously there had been a healthy stomachlining.

Soon after Marshall published the result of his self-experimentation, he was able to obtain funding for a more detailed experiment to determine the role of H. pylori in stomach disease. Marshall and Warren went on to work out the way the bacteria cause infections and disease. They also determined why many people harbor the bacteria in their stomachs, but never develop disease. Other researchers confirmed their findings, and by the early 1990s, the role H. pylori played in stomach ulcers and chronic gastritis was well established. For their research, Marshall and Warren shared the Nobel Prize for medicine in 1995.

These stories dramatically illustrate medical research using human volunteers. At the time James Carroll and Jesse Lezear contracted yellow fever, medical research using the scientific method was scarcely a few decades old. No guidelines on using human volunteers existed when Carroll exposed himself to a deadly disease in the name of science. Many decades would elapse before guidelines established what truly constitutes informed consent.

The physicians of the Yellow Fever Commission knew they would need to obtain consent of the volunteers. When approached, both U.S. Army soldiers and Spanish immigrants consented to be part of the yellow fever experiments. The consent documents established a contract between individual volunteers and the Yellow Fever Commission, represented by Reed.

Each volunteer was at least 25 years old and each explicitly volunteered to participate in the research. The documents discussed the near certainty of contracting yellow fever while being in Cuba versus the risks of developing the disease as part of the experiment. The volunteers received promises of expert and timely medical care, and the volunteers had to remain at Camp Lazear, the site of the experiments, for the duration of the studies. The volunteers received $100 “in American gold,” with an additional $100 if they developed yellow fever. This money represented a near fortune for a poor Spanish immigrant or an underpaid Army private. A family member could receive the money in case of death, but if the volunteer deserted prior to completion of the experiment, they forfeited all payments.

This consent is quite coercive by the standards of today. Essentially, the volunteers heard that they would likely get yellow fever anyway, so if they volunteered they would receive both money and better medical care than the average soldier or immigrant would likely obtain. No organization overseeing human research would allow such a means of obtaining volunteers for research today. This “informed consent” has elements of coercion, forceful persuasion, and manipulation, particularly in the military situation with officers asking enlisted personnel to participate. However, the involved physicians truly put themselves first in line, and at that time, obtaining any consent was remarkable.

The modern practice of informed consent in human research did not come into being until after the revelations of the horrific abuse of human subjects the middle of the twentieth century. The well-documented atrocities committed by German and Japanese physicians during World War II (1939–1945) have made the names Josef Mengele and Shiro Ishii synonymous with torture in the name of medical science. Perhaps less well documented are the experiments during World War II by American physician Stafford Warren. In attempts to learn of radiation effects, researchers injected plutonium into humans without their consent. Experiments on American troops using mustard gas were conducted with the “volunteers” not knowing what they were volunteering for. Unlike the example of Carroll, none of the physicians involved in these experiments stepped forward to experiment first on themselves.

Knowledge of the abuse of human subjects in the Nazi concentration camps resulted in the drafting of the Nuremburg Code. Perhaps one of the most important of the ten principles in the Nuremburg Code is the assertion that consent to participate in medical research must be given free of coercive influence. Also directed in the codes is the assertion that the benefits of the research should exceed the risk to the human volunteers.

Issue and Impacts

In 1964, medical leaders drafted another somewhat more thorough set of guidelines known as the Declaration of Helsinki. This document sets forth ethical principles for medical research involving human subjects. The declaration—amended several times and most recently in 2004—together with the Nuremburg Code sets forth the ethical principles to which medical research using human beings must adhere.

Marshall discussed the ethics of his decision to experiment on himself in his Nobel Lecture. Marshall stated, “I had to be my own guinea pig.” He felt that he was the only one who could make truly informed consent to his own experiment, and this thinking confirmed his approach to the problem of using human subjects to prove the role of H. pylori in stomach disease. He clearly felt the benefits outweighed the risks.

Modern medical researchers delve into diseases involving very deadly bacteria and viruses. Experimental designs minimize the risks of exposure to these pathogens. Special containment facilities (biosafety laboratories) ensure that accidental exposures do not occur easily. Special animal models are built by genetic techniques, negating the need for experiments such as those used by Carroll. Still, a need will certainly always exist for courageous individuals to take great risks in order to solve serious medical problems.

BIBLIOGRAPHY

Books

Pierce, John R., and James V. Writer. Yellow Jack: How Yellow Fever Ravaged America and Walter Reed Discovered Its Deadly Secrets. Hoboken, N.J.: John Wiley & Sons, 2005.

Web Sites

Marshall, Barry J. Nobelprize.org. “Nobel Lecture: Helicobacter Connections.” 1995. <http://nobelprize.org/nobel_prizes/medicine/laureates/2005/marshall-lecture.html/b> (accessed June 3, 2007).

National Institutes of Health. “Guidelines for the Conduct of Research Involving Human Subjects at NIH.” <http://ohsr.od.nih.gov/guidelines/guidelines.html> (accessed June 1, 2007).

University of Virginia Health System. “Yellow Fever and the Walter Reed Commission.” <http://www.healthsystem.virginia.edu/internet/library/historical/medical_history/yellow_fever/index.cfm> (accessed June 1, 2007).

Lloyd Scott Clements

Infectious Diseases: In Context