One Colombian's Quest For A Malaria Vaccine

In March of this year, Colombia heard some important news that had nothing to do with the country’s infamous drug trade. A Colombian scientist named Manuel E. Patarroyo published a study in Nature showing that an experimental vaccine he had developed was tantalizingly effective against malaria, a disease that threatens two-thirds of the world’s population. Until then, the parasite that causes malaria had stubbornly resisted the efforts of hundreds of researchers in the U.S. and Europe to develop a vaccine. So how was a relatively obscure scientist from the Third World—one who has been forced to cope with poor funding, inadequate facilities, even terrorists—able to achieve the first promising results? The answer is that innovation and creativity aren’t found only in well-funded, prestigious laboratories in the developed world. Patarroyo’s approach to creating a vaccine, for example, was particularly novel. He devised a mixture of three different synthetic peptides, each a copy of a malaria protein. In effect, the mixture gives inunune cells a description of the malaria parasite—sort of a policeman’s composite picture—with which they can hunt the pathogen down. “In a few years of work, Patarroyo has come up with interesting and important results,” says Peter Perlman of the University of Stockholm, one of the world’s top malaria researchers. Hard Work Perhaps just as impressive as the vaccine results has been Patarroyo’s ability to inspire, cajole, pull strings in high places— and, against all odds, put together his 30-scientist Instituto de Inmunologia in Bogota. Conditions at the institute might surprise a scientist from the U.S. “Disposable” supplies such as pipettes are used, washed, and reused, and research must be scheduled around regular shortages of basic supplies like agar and test tubes. But the lab is equipped to do sophisticated peptide sequencing, analysis, and synthesis; and it has managed to persevere and thrive. “We work very hard in the lab,” Patarroyo says. “Most Colombian people work very hard, but because of the wrongdoing of a few, the world thinks all Colombians are drug traffickers.” Patarroyo’s dark-horse arrival into the scientific limelight hasn’t been a complete triumph. A number of better-known malaria vaccine researchers say they want to see more results before they acknowledge the Colombian scientist’s achievement. Some have even taken Patarroyo to task for what they call unethical treatment of his human subjects, specifically allowing malaria parasites to reach dangerous levels in the volunteers. And he faces vociferous opposition to his ideas from competitors at the Colombian Instituto Nacional de Salud—although he has managed so far to steer clear of a scandal that has implicated some of his Colombian rivals (see story, page 27). Whatever he is to the world of science, however, among most of his countrymen, the slight, wiry, balding, 41-year-old Patarroyo is a hero. Frequently appearing in newspaper stories and on television, the scientist is as well known to his compatriots as is their president. In a popular magazine’s survey, for example, he was third on a list of people Colombians want most to be like. A high school boy who has seen him on the news admiringly says, “Le saca el jugo”— “He sucks the juice (from life).” The oldest of 10 children born to storekeepers in rural Ataco in southeast Colombia, Patarroyo was deeply affected by a serious bout with tuberculosis when he was only nine. The experience remains “a waking nightmare,” he says. “It’s like a sword of Damocles; I’m always wondering whether I’ll ever contract it again.” But the grim days of illness brought him a career. As soon as he recovered, Patarroyo began an obsessive study of diseases. Nine years later, in 1965, he entered the School of Medicine at the Universidad Nacional de Colombia. He went on to postdoctoral studies at Rockefeller University in New York City. There he worked under immunologist Henry Kunkel, who helped him both professionally and financially. People liked the bright, inquisitive young Colombian. John Zabriskie, a virologist at Rockefeller, remembers thinking that, “if anyone could make it in research in Colombia, it would be him. He had inner drive, he wouldn’t take no for an answer. He had the determination to foster something in his own country.” Kunkel urged Patarroyo to work on problems affecting people in Colombia. At the time, Zabriskie was looking for cell-surface markers that denoted susceptibility to rheumatic fever. Rheumatic fever is a major health scourge in Colombia, and Patarroyo, still in his twenties, returned to Bogota to devote energy to the problem while doing clinical work at the Hospital San Juan de Dios. When Zabriskie visited him later in his tiny, one-room lab in the hospital, a room also used for doing lab tests and pathology, it was clear that an uphill battle lay ahead. “He had scraped together and bought himself a used centrifuge and a microscope,” Zabriskie said. “He was very broke for a long time.” Then good luck came disguised as misfortune. Doctors at San Juan de Dios illegally went on strike, and the president of Colombia closed the hospital. No one knew how long the strike would last, and electricity and water were still available. Hospital officials looked the other way while Patarroyo secretly continued to use his lab in the abandoned hospital to collect blood samples from pregnant women at a nearby lying-in hospital. The blood samples proved to be valuable—both scientifically and financially. Women who have many children are more likely to make antibodies to rheumatic fever cell-surface markers than their less fecund counterparts. And since women in Western countries typically have few children, and are not exposed to rheumatic fever, laboratories in the U.S. and Europe need antibodies from the Third World for their work on the disease. Patarroyo found a cheap method of screening the blood samples for the desired antibodies and sold them to laboratories in the U.S. and Europe. “I realized I was sitting on a gold mine,” he says. By 1977, he was pulling in $5,000 annually from rheumatic fever antisera, not a large sum by U.S. standards, but enough to expand his work. He began looking for susceptibility markers for other serious local diseases: leprosy and tuberculosis. Soon afterward, Peter Goldmann, the South American coordinator of the German Leprosy Foundation for the past 15 years, was persuaded to visit the lab. He noticed that the lab was staffed with young, enthusiastic undergraduates and graduate students from the Universidad Nacional de Colombia. They called Patarroyo El Jefe (The Boss) and worked for $100 a month or even volunteered their time. Goldman was deeply impressed and decided that the foundation should support the 30-year-old scientist. “Patarroyo had refrigerators and microscopes, nothing sophisticated,” Goldmann recalls, “but he had attracted a number of young people, all from different specialties. There was an atmosphere of liberty, everyone working in an open style.” Marcella Parra, now a malaria researcher at the U.S. National Institutes of Health, was one wham Patarroyo inspired. When she applied to the lab, “He said, if you are ready to work more than 24 hours a day, and more than seven days a week, you’re more than welcome here.” The Leprosy Foundation’s $3,000 donation enabled expansion into adjacent rooms in the abandoned hospital. When San Juan de Dios finally reopened in 1978, Patarroyo had taken over the entire ninth and eleventh floors of the building. The hospital chiefs were faced with a dilemma. What were they to do with Patarroyo, now that they needed the hospital again? Their solution was to offer the scientist the original San Juan de Dios hospital building, an ancient, French-style, three-story wreck, which had been abandoned for at least 20 years. Although the building’s mansard roof had caved in and debris lay a yard thick on the first floor, Patarroyo gladly accepted the building—and with it, the responsibility to renovate it for his own research needs. For funds, he sought the assistance of then-president Belisario Betancur, who turned the request over to his top financial adviser, Diego Pizano Salazar. As an economics student at Cambridge University, Salazar had roomed with a French physicist who had impressed him with the value of good research. When he found that Patarroyo had published his rheumatic fever marker research in Nature, Salazar was convinced that the scientist deserved support. He recommended that $200,000 come directly out of the national budget for the new lab. Soon Patarroyo and his young band of workers had a new roof, plumbing, and three floors of laboratory space all to themselves. Salazar continued to be helpful. He deftly procured a $1 million SmithKline Beckman protein sequence and introduced Patarroyo to oil magnate Armand Hammer, a meeting that resulted in $150,000 in donations. Salazar then organized an international immunology conference in Bogota, attended by such luminaries as Nobelists Bruce Merrifield and David Baltimore. Sophisticated computer equipment followed. By 1981 Patarroyo’s Instituto de Inmunologia was finally ready to operate and compete on an international level. And the scientist decided to take on one of the biggest health problems in his country—malaria. Between 1,000 and 2,000 of the 500,000 annual Colombian malaria cases are fatal. At the time, a number of well-funded centers in the U.S. and Europe had been looking for a malaria vaccine, many on grants from the World Health Organization. (WHO) and the Agency for Inter national Development (AID). With a budget that was only a fraction of most Western labs, the insitution decision to join this race seemed naive. But the long odds didn’t stop Patarroyo. He first established monkey research facility in an abandoned building in Leticia that had once been used to illegally export animals from the Amazon city. Now about 100 aotus (owl) monkeys are kept there at any given time. Aotus monkeys are an excellent model, even more susceptible to malaria than humans, and almost always die if left untreated. Patarroyo’s facility is as well-maintained as any of NIH, according to Parra, and the monkeys live in their natural climate, eating their regular diet. Yet by modern standards, the facility costs ridiculously little to maintain: about three dollars a year for rent and a few hundred for labor and food. “We have always made advantages from our disadvantages,” Patarroyo says. In 1986 and 1987, Patarroyo’s team inoculated hundreds of aotus monkeys with experimental synthetic proteins designed to imitate bite of malaria proteins. Might one, or some combination, of the peptides be an effective vaccine? Parra recalls this time in the Bogota lab as “extremely hard work.” “Four nights a week, we would stay almost all through the night, to three and four in the morning,” she says. “I spent about 18 to 20 hours a day in the lab.” In August 1987, Patarroyo reported in Nature that three particular synthetic proteins protected a significant proportion of monkeys. There were problems, however. A carrier molecule used to present the peptides to the monkeys’ immune systems appeared to damage the animals’ livers. So Patarroyo turned for help to molecular engineer Tom Blundel of Birk- beck College in London, who sent colleagues to consult on alternative ways of delivering the vaccine. In addition, Patarroyo sought inspiration from a much less likely source. He frequently goes on “survivalist” missions, journeying up the Amazon for days with nothing but a fishhook to gather food. “I find that I do some of my most clear thinking in the jungle,” he says. This time, he took along two of his English colleagues for a week-long visit to the Amazon. The strategy worked. On a muddy Amazon River beach, Patarroyo and his English colleagues conjured up two different ways to polymerize the peptides into a neat molecular package that could enter the bloodstream without the harmful carrier molecule. The resulting vaccine was tested in monkeys with great success. The next step was a human trial, a prospect that frightened the Colombian scientist. “I could not sleep for weeks, thinking about all the things that could go wrong,” he recalls. An ethics committee, chaired by Colombian Vice-Minister of Health Oscar Rojas, oversaw the trials. The committee adopted WHO guidelines for human vaccine experiments, which specify that any subject who reached a parasitemia, or blood concentration of parasites, of 0.5% had to be treated and removed from the study immediately. Setting the parasitemia limit affects the outcome—and credibility—of any trial. If the limit is too high, the subjects’ lives are in danger; if it is too low, the trial might not progress long enough to judge the efficacy of the vaccine. Some scientists, however, consider the WHO guidelines to be high, because the parasite can hide in blood vessels, then multiply unexpectedly and dangerously. Risky though the experiment was, 100 soldiers in the Colombian army volunteered for the trial. Presumably, being injected with malaria was seen as being less dangerous duty than fighting insurgents in the countryside. Patarroyo chose 13 of the soldiers. One group received the first version of the vaccine, and the second received the other version. The third group received a placebo. All were injected with live parasites. If the anticipation of the experiments was agonizing for Patarroyo, the reality was even worse. “The idea that my experiments might be responsible for a human life—it was killing me,” he remembers. But by the end of the second week, it became clear that one of the vaccine preparations was a qualified success: three out of the five soldiers in that group recovered without treatment. “When it began to look as though the trials were a success, I was flipping over,” says Patarroyo. The other version turned out to be ineffective. All the soldiers who became sick were treated and released without mishap, and are still followed by the Ministry of Health. One now works in Patarroyo’s lab. The Colombians’ euphoria over the success of the first vaccine, however, was dampened by the reaction of some scientists. Nature printed a commentary along with Patarroyo’s paper in which Louis Miller, an NIH malaria researcher, criticized the Colombians for allowing some of the study subjects to reach parasitemia levels higher than the WHO guidelines allowed. Patarroyo admits that this did happen. But abrupt spurts of parasitemia are characteristic of malaria, he says in his defense, and they occurred between regular and frequent checks. As soon as the high levels were detected, the volunteers were immediately treated, the scientist says. Acid Test Other scientists were more generous. Margaret Perkins, a malaria researcher at Rockefeller Institute, feels that Miller treated Patarroyo unfairly. ‘This is the first positive result in the field of malaria vaccines,” she says. “But every word in the [commentary] was negative.” The acid test, of course, is whether Patarroyo’s results can be replicated. The answer shouldn’t be long in coming. The WHO is now helping to support Patarroyo’s research and is funding confirmatory animal studies of the original work at the Centers for Disease Control in Atlanta. The experiments began in September. Meanwhile, Patarroyo’s lab is thriving. The Instituto’s budget has doubled to $600,000 this year, and the laboratories will expand into adjacent buildings. Simultaneously, Patarroyo will hand over the responsibility for some operations to colleagues returning from fellowships in Western countries. His methods of bringing along young researchers are admired nationwide, and have been officially adopted as a policy of the Universidad Nacional. But still, there are reminders that life for Third World scientists holds surprises not typically found in the U.S. or Europe. Soon after the vaccine trials were published, Patarroyo was contacted by the M-19, a terrorist group responsible for the 1986 execution of 13 Colombian Supreme Court judges and the destruction of the Palace of Justice. They feared that Patarroyo’s collaboration meant the vaccine would benefit only the military. Taken by a terrorist to a hidden meeting place two hours outside of Bogota, Patarroyo tried to convince his abductors that the fruits of his work are for everyone. It worked frightened but unscathed, he was released. John Lauerman is a freelance writer based in Boston, Mass.

One Colombian's Quest For A Malaria Vaccine

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