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Fever Pitch
A physician recalls his work in a World War II research project aimed at stamping out malaria.
by Curtis Prout

In the last years of World War II, I played a small part in what may have been one of the largest medical research projects of that war. Our goal was formidable: to conquer malaria, a disease many thought was unconquerable. We did not, unfortunately, achieve that goal. But the story of our project may interest, perhaps even encourage, contemporary researchers while also providing a picture of the concerns, setbacks, and small triumphs that were part of what was known as the Malaria Project.

In the Heat of Battle

It was apparent early in the war that malaria was going to be a scourge to Allied troops, especially in their operations in North Africa and the Pacific. By 1942, the illness had incapacitated half of General Douglas MacArthur’s active-duty forces in the Southeast Pacific, hobbling the commander’s efforts to advance north from Australia and New Guinea. By the war’s end, an estimated 60,000 military personnel had died of malaria in those theaters.

One reason the casualty numbers were high was the lack of an available, effective treatment. Prior to the war, quinine was the most common antimalarial in use. Extracted from the bark of cinchona trees, quinine had originally been harvested from wild trees in the jungles of South America. Since the eighteenth century, however, the drug had been produced from trees cultivated on plantations throughout Southeast Asia. When this region came under Japanese control in the 1940s, the world’s access to quinine was cut off.

Synthetic alternatives were limited; quinine’s effectiveness and low cost had squelched profitability—and thus research—prospects. Although there had been some development in the 1930s, the results, such candidates as chloroquine and atabrine, sat untested on the shelves of manufacturers, including I. G. Farben in Germany and Winthrop Chemical Company in the United States.

The quinine blockade and the toll malaria was taking on U.S. troops spurred the U.S. Office of Scientific Research and Development, or OSRD, to initiate the Malaria Project in 1942. The project enlisted a stellar list of U.S. researchers, including infectious disease expert Lowell Coggeshall and immunologist Michael Heidelberger.

I first learned of the project in December 1943. I was a junior resident at the Johns Hopkins Hospital and had been summoned to the office of Warfield Longcope, the physician-in-chief. I was nervous, fearing a reprimand for some medical error I had unknowingly committed. But my worries were short-lived as Longcope began by telling me of an urgent call for researchers ineligible for military service and qualified to work on a project aimed at finding a cure for malaria. Would I be interested?

I accepted immediately. I had expected to head for the tropics for this research but soon learned that decision makers in Washington, DC, felt that the factors of immunity or partial immunity in areas endemic for malaria would interfere with the evaluation of any antimalarial medications. The project’s five clinical testing areas would instead be stateside. I was given a choice between the state prison in Joliet, Illinois, and the Boston Psychopathic Hospital, which was later renamed the Massachusetts Mental Health Center. With my wife and our two small children in Boston, I naturally chose the latter.

The Boston unit was headed by Allan Butler ’26, a professor of pediatrics at Massachusetts General Hospital, and supported by two senior physicians at the hospital: Augustus Rose ’32 and Lawrence Trevett. The unit’s personnel roster was rounded out by three young physicians eager to help the war effort: Arthur Linenthal ’41, Joseph Hindle, and me.

The unit’s testing facilities were split between Boston Psychopathic and a ward at MGH. At MGH, Linenthal was to test and observe any effects of the antimalarial candidates on conscientious objectors who had agreed to work at the hospital in lieu of being forced into the military—or jailed for their refusal. At Boston Psychopathic, our unit was to test the effectiveness of the antimalarials against the disease itself. Our subjects were psychotic patients selected from the populations of the dozen or so large hospitals overseen by the Massachusetts Department of Mental Health. Hindle and I were assigned to this hospital.

The Good, the Bad, and the Ugly

The idea of using psychotic people as test subjects for malaria research was ingenious, bizarre, and, especially by today’s standards, unethical. With what justification could we give a dangerous infectious disease to these people without informed consent? Well, at that time there were no ethics committees, and a standard for informed consent in biomedical research had yet to be broadly articulated; The Nuremberg Code, an outcome of the era’s war-crimes tribunals, wasn’t assembled until 1948.

But there was a solid scientific rationale to this approach. Before penicillin, 10 percent of all patients in the mental hospitals in the developed world were suffering from late syphilis of the brain, known as general paresis of the insane, or, simply, paresis. Arsenic and bismuth, moderately effective in other forms of syphilis, did not affect paresis. In Vienna in 1917, Julius Wagner-Jauregg observed the effects of malaria on people with paresis; some paretics who contracted malaria improved greatly. His work resulted in cure or improvement for many thousands of psychotic paresis sufferers and earned him a Nobel prize in 1927. At the time, it was thought the illness’s fever was effective against paresis, but later investigations showed the effect was probably a result of immunity to antigens shared by the treponema of syphilis and the malaria parasite.

By the 1930s, hospitals throughout Europe were administering malaria to paretic patients with encouraging results. In this country, the center for malaria therapy for paresis was the Johns Hopkins Hospital. By the 1940s, when OSRD was deciding how to structure the Malaria Project, the malaria treatment of paretic patients, in which quinine was used to successfully terminate the infections, was an accepted standard.

OSRD studied the procedure and approved the use of paretic patients. The project was to use an allegedly “tame” strain, and quinine was to be kept on hand should the experimental medications previously tested on the conscientious objectors prove ineffective at stemming malarial infections. Although decision makers in Washington may have harbored objections to the ethics of this approach, the urgency of the wartime situation trumped their concerns.

Into the Breach

The antimalarial candidates, and even the malaria strains we tested on the subjects in our unit, came out of the research laboratories of pharmaceutical companies, academic chemistry departments, and at least one cosmetic manufacturer. Approximately 13,000 candidate compounds were developed for the project; most were hastily tested for toxicity in animal models. Malaria strains were also tested; avian strains were evaluated in domesticated fowl, and human strains were tested on dogs and monkeys. The outcomes of these trials, unfortunately, were rarely shared with the clinicians who administered the candidate antimalarial agents. In addition, compounds effective against animal malaria were usually not effective against the human form and vice versa.

Once we had administered the candidate compounds to our group of conscientious objectors and had inoculated our paretic patients with malaria and provided them the selected antimalarial, we focused on monitoring the effects of the agents. Linenthal would monitor his charges for changes resulting from the antimalarials, and Hindle and I would check our patients for disease progression after treatment.

The daily routine at Boston Psychopathic wasn’t arduous. We would carry out daily rounds, physical examinations, blood counts, and parasite counts for which I devised a logarithmic scale for charting the daily levels. From time to time, one of the senior hospital physicians, either Rose or Trevett, would come by for rounds, and once a week, Butler would meet with Linenthal, Hindle, and me before departing to Washington to report on the results of our testing.

The testing protocol we followed began when we inoculated our paretic patients with an attenuated strain of Plasmodium vivax, the least virulent of the Plasmodia strains to cause malaria. When the fevers began to cycle every 48 hours and the parasite counts reached a predetermined level, we would administer an experimental drug that had been tested on the conscientious objectors. Then we would carefully watch parasite counts, fever, and the patient’s general condition. If the disease continued unchanged after about a week, we would terminate it by giving the patients a dose of our closely guarded supply of quinine. After a suitable period of observation, most patients returned to the state hospital from which they had come, and we never saw them again.

Even today I am troubled by the fact that I never knew what happened to those patients. We perpetuated the malaria strain we used by taking blood from infected patients and injecting it intravenously into new arrivals. How many patients, I wonder, later developed hepatitis or other diseases as a result of this practice? And because P. vivax has been known to relapse years after its first attack, how many suffered subsequent attacks—an outcome for which, at the time, there was no therapeutic recourse?

War Stories

Although at my darkest times I felt I wasn’t contributing to the war effort, our work did produce two scientific papers. One was among the first studies to show that penicillin was ineffective against malaria while another demonstrated the effectiveness of penicillin on paresis.

Some of the more interesting results were unpublished; they arose from observations of the responses that the conscientious objectors had to the various antimalarials. One example stemmed from the testing of a compound developed by Louis Fieser, a professor of organic chemistry at Harvard College, where he was also the chief liaison to OSRD. Tests of Fieser’s products usually were unsuccessful, and this candidate had been no exception. Fieser, however, was unsatisfied with the results and insisted we use larger doses for longer periods than our protocols permitted. Despite his insistence, the only effect the compound induced was a deep crimson staining of the blood plasma, which caused those receiving it to look exceptionally pink and healthy for several weeks.

Another compound had a somewhat startling side effect: The hair of the 20 or so men testing it became white at the roots. And their hair continued to grow out white until the drug was stopped. Thus, some of the conscientious objectors developed a broad albino stripe that was bordered by their normal hair color—an appearance that gained them the nickname “skunks,” a moniker that vanished when their original hair color grew back. Near the end of our project in 1945, chloroquine, tested by one of the other units, was proving to be marvelously effective. We had been simultaneously testing its bromine analog. It showed itself to be as effective as chloroquine against the parasite but more costly and less safe, so it was not developed further.

More than 60 years have passed since the Malaria Project ended, and research on the disease continues. An estimated 247 million cases of malaria are reported globally each year. One million of those cases, mostly children under five years, die from the disease. It is my hope that knowledge of this project may aid science’s efforts and ultimately help to conquer what still seems unconquerable.

Curtis Prout ’41 taught physical diagnosis at Harvard Medical School and Brigham and Women’s Hospital for many years, served as assistant dean for students at HMS, and was chief of medicine at Harvard University Health Services. Now semi-retired, Prout has an internal medicine practice in Manchester, Massachusetts.

Photo caption: Colonel Arthur Fischer and Brigadier General James S. Simmons watch as gardener G. A. Seaton wraps cinchona seedlings for shipment from Washington, DC to South America in November 1943. Cinchona bark is the source of quinine, which is used in the treatment of malaria.

Photo: National Library of Medicine