by Bill Shore
. . . And she sucked up something else as well: some protozoan stowaways.
The mosquito, in a simple act essential for reproduction, ensures the reproduction and spread of another species: the Plasmodium parasite.
The malaria cycle begins once more.3
Compared to the toll taken on human beings, the toll on the mosquito is minuscule: The mosquito herself gets off quite easy, an unwitting carrier of destruction. It is inside of our bodies that the real carnage takes place.
A mosquito transfers about 10 percent of the parasites it is carrying when it takes that next bite. These sporozoites travel through the blood and reach the liver in less than thirty minutes. In the liver, all hell breaks loose.
The sporozoites, safe in the liver, form “schizonts,” large, multinucleated cells that divide and multiply. When the schizonts burst, they release as many as 40,000 merozoites. If there was a factory anywhere in the world that consistently produced product at this rate it would be the globe’s dominant brand, which is exactly what malaria is in Africa: the dominant brand-name disease.
By the seventh or eighth day, the liver cells release the merozoites, which head for red blood cells to finish their deadly mission. The merozoites trigger a reaction from the B cells of the host’s immune system. Many of the merozoites are destroyed, but those that escape invade the red blood cells. It is when the merozoites burst out of the liver and head into red blood cells that the host spikes a high fever. The parasite forms knobs on the exterior of a red blood cell, which allows it to adhere to cells lining the blood vessel and ultimately impede blood flow.
In her book Diseases and Human Evolution, paleopathologist Ethne Barnes explained that “the disk-shaped red blood cells are responsible for transporting life-giving oxygen from the lungs throughout the body tissues and taking away the gas waste product of cellular respiration, carbon dioxide, to the lungs to be expelled. . . . As the number of merozoites increases, the number of viable, circulating red blood cells decreases, producing anemia in the host.”4
The red blood cells themselves soon burst, releasing more merozoites, which invade fresh blood cells, and the cycle continues, over and over, until billions swarm in the blood.
The parasites replicate in the blood every forty-eight hours, and each one has the chance for mutation. As Carole Long, chief of malaria research at the National Institute of Allergies and Infectious Disease, said, “the parasite you put in is not necessarily the parasite you get out.”5
WHERE THE WILD THINGS ARE
Hoffman’s work isn’t the only exciting development in malaria, just the boldest and most imaginative. In fact the field is alive with laboratory research, clinical trials, field studies, and conferences. The World Health Organization is now tracking thirty-five separate vaccine-development efforts. One of these is with a former Hoffman collaborator at the Walter Reed Army Institute of Research.
His name is David Lanar, and I decided to visit him. After all, Walter Reed’s research facility was in Silver Spring, only a hop, skip, and jump away from Hoffman’s strip-mall offices. As I arrived for my appointment, I noticed a sign just past the institute’s main gate announcing that I was in a restricted area and that federal law prohibited me from taking notes on any of the activities therein without the express permission of “the Commander.” Security at the various checkpoints was relaxed but thorough. Pairs of soldiers in camouflage fatigues passed by as I waited for Lanar, who was coming up on his twentieth year in immunology at Walter Reed. Despite the posted warnings, he seemed more than happy for me to write down every word he said.
When Lanar arrived in the lobby, he looked like Maurice Sendak’s version of a parasitologist, something right out of Where the Wild Things Are. He was a heavy-set, round man made up of equally heavy and round constituent parts. He had a large and friendly face, with only his eyes and his ruddy cheeks visible through a crown of black and gray hair and a beard. He had massive hands, and a white button-down shirt strained over his barrel-chest. It was open at the neck, at the sternum actually, and rumpled all the way down to where it was ambivalently tucked into his faded black Levi’s. The grey hairs of his chest sprouted through his collar as though reaching up to unite with his scruffy beard.
His pride in the building and its mission was quickly evident. Walter Reed is a massive facility that employs 1,200 researchers, many of them civilian, and almost 400 of the 1,200 are working on malaria. “It is the largest number of malaria researchers anywhere in the world,” Lanar explained. “This is also where they bring suspected anthrax for testing.” He pointed out a vaccine manufacturing facility across the street that enabled Walter Reed to create vaccines without depending on the large drug companies.
Trained at the London School of Hygiene and Tropical Medicine, Lanar had been at the National Institute of Health, working on other parasites—Leishmania and Shistosomiasis—but left to join the army because of its labs and capacity. Like many tropical medicine docs, he is cast against type for the U.S. military, but there’s not much of a market for private practice in this field. Those who want to work in it and want to have the tools necessary for success learn to salute and join one of the largest bureaucracies in the world.
When we got to his office, which was crowded with books and files, I asked why the interest in global disease and malaria had been increasing recently. He and his office mate, Ann Stewart, seemed aware of the revived interest in malaria but only vaguely, as if developments in the world beyond their microscopes were merely distant, rumored events. Stewart, who had a stuffed toy monkey draped over her microscope, attributed some of the increased attention in global health and neglected diseases to the Gates Foundation and the Harvard School of Public Health. She described a compelling dramatization of the continuing imbalance in investment that was presented by Amir Atarran, a lawyer and immunologist who writes and lectures on global health.
Attaran would take the stage with a large jar and a supply of small, round BB’s. He would drop in the few that he said represented the world’s investment in neglected diseases like malaria, and then he would pour the amount that he said represented the world’s investment in HIV. Apparently he would stand there pouring for quite some time, with the racket getting louder and louder, until the point could not have been missed.
Lanar’s focus, like Steve Hoffman’s, is the development of a malaria vaccine, and for the same reason: Malaria has become resistant to almost all of the drugs that have been developed to fight it, “but we’ve never had a malaria vaccine so we don’t know how it will react.” The research process with new vaccines usually goes from table top to animal to human. But “there is no way to conduct animal experiments” with malaria vaccines, Lanar said, “because falciparum malaria is unique to humans. Obviously the FDA has tremendous confidence in our approach, otherwise they would never let us challenge human beings.”
Lanar and Stewart described what is known as “the hotel phase” of clinical trials. Volunteers that have been vaccinated are “challenged” with malaria by being subjected to mosquitoes until they are bitten a sufficient number of times. These aren’t just any mosquitoes, though; they are carefully chosen ones that are in a small box that is placed over a volunteer’s arm—five to a box, each carrying the parasite. The volunteers then check into a hotel with physicians who examine them twice a day for about two weeks. If a significant percentage of those who have been vaccinated resist the disease, the experiment is deemed a success. Those who show symptoms are treated immediately and effectively.
Lanar was cautiously optimistic about the vaccine he had been developing. Known as LSA-1, the liver stage antigen, it attacks the parasite at a mature stage of its development. But he was quick to suppress expectations. Lanar told me of the five years he had spent building the vaccine and said, “I was convinced it was going to make the cover of Science magazine. But the vaccine failed, and I have to tell you I got really depressed. I was clinically depressed for quite a while.”
It
’s not surprising. Parasitologists tend to be obsessively committed to their task. Lanar had a stained-glass piece depicting the Trypanosoma parasite, which is transmitted by a tsetse fly and causes Chagas’ disease, hanging in his office window. It showed the parasite defecating and invading the heart muscle, all in glorious sun-streaked colors. Lanar had made it himself, and the brightly colored bits of glass seemed symbolic of his devotion to his work.
He oversees a handful of researchers in a lab that is one of about forty on a campus that also includes a vaccine manufacturing facility to support the army’s own clinical trials. “They do the work and I write it up. That’s all I do is write,” he said, referring to both medical journals and the grants that must be written to request funds.
“One of the things that is different about us,” emphasized Ann Stewart, “is that our focus is on the adult military traveler. But most of the interest today is on children in Africa, and frankly that’s probably what really motivates most of the people who work here.”
The military only funds about one-third of the work at Walter Reed. The rest comes from donors or partnering companies.
It would be hard to picture two greater opposites than David Lanar and Stephen Hoffman. Both made their way to the vaunted London School of Hygiene and Tropical Medicine, the Harvard of tropical disease, and joined the military to pursue a passion, but the similarities end there. Lanar is an institutional man, trading independence and potential notoriety for the security and resources the army can provide. Hoffman, neat and trim, politically deft, has to run his own show. Impatient with conventional wisdom and the confines of institutional processes, he is the classic entrepreneur, unleashed, a jay walker, making his own rules as he goes, undeterred by others’ definitions of possible and impossible.
“Steve’s a smart guy,” Lanar told me. “He used to work right here. But what he’s trying won’t work.”
A MASTER SPY’S MICROSCOPIC TRADECRAFT
“I’ve always been a bit of a spectrometrist,” professor Paul Roepe confided to me in the privacy of his office, just as one might admit, but play down, an unusual fetish or eccentricity. It was his way of explaining how, as a Ph.D. physicist turned molecular chemist and cellular biologist, he’d ended up inventing a revolutionary process for determining how deadly parasites became drug resistant—for actually seeing the treachery their molecules committed inside of red blood cells.
If Steve Hoffman and other vaccine developers are the generals of the malaria battlefield plotting the best strategy for repelling invasion, then Roepe is director of central intelligence. His reconnaissance critically informs where to fight and what weapons to use. Roepe and his colleagues designed the equipment that enables us to spy on the parasite. Though technologically complex, it is based on spectroscopy, which measures the diffusion of light.
Observing the malaria parasite is essential to understanding both how to stop it and how it resists being stopped. The malaria parasite is so tiny that it is extraordinarily difficult to observe. It grows inside of individual red blood cells that have a diameter of about 7 microns. A micron is one ten-thousandth of a centimeter. And the parasite itself isn’t even a micron in diameter.
The ability to resist the drugs that are developed to defeat it has enabled the parasite to survive for tens of thousands of years. This ability is shared by other parasites as well as bacteria, tumors, and other diseases. Consequently, the intelligence Dr. Roepe is gathering is coveted by leading medical experts in every field and will almost certainly have long-term applications to cancer, methicillin-resistant staph infections, HIV/AIDS, and the like.
His third-floor office was sandwiched between several small, busy labs at Georgetown University’s Basic Science Building. On the door was taped a scrap of white paper that said “2 million children die of malaria every year.” Next to it was a copy of an obituary for Arthur Kornberg, a mentor of Roepe’s and a Nobel Laureate whose work studying enzymes helped scientists manufacture cells and create the field of biotechnology. On the wall inside were drawings from Roepe’s son and daughter, aged nine and twelve.
Dressed casually, Roepe had the lean body of the competitive triathlete that he is. His head was shaved and he sported a two-day growth of beard. He resembled a less menacing version of the actor John Malkovich. He wore a yellow LiveStrong band on his left wrist, and he had used a pen to write a scribbled note to himself on his palm.
When I’d e-mailed Dr. Roepe to request an interview, he had consented but said, “I don’t see what this has to do with your work and I’m puzzled about what you think I can tell you of interest.” I gathered he was a man who didn’t like to waste time.
He certainly didn’t waste any during his formal education. His career seems to have followed a meticulously plotted path. He was especially purposeful about pursuing multidisciplinary studies across physics, chemistry, and biology. But serendipity also played a critical role.
I asked if there was any science background in his family:No, my father was a small town lawyer and judge. But my grandfather was a glass blower. He came here from Scotland. And at the beginning of World War II he realized that the army was going to need syringes and in those days they were all made of glass. So he started making them. That grew into a pretty big glassware products company that supplied a few of the large pharmaceuticals. I remember going to the factory with him and being fascinated by all of the equipment, the glass tubes and beakers and coils. That’s when I knew I was going to be a chemist.
After getting his degree in chemistry at Boston University, and then a Ph.D., he did a post-doc at the University of California at Los Angeles and ended up working on tumor drug resistance. He was offered a position at Sloan Kettering in New York, where he worked from 1990 to 1997. He had a corner office with two large windows. By chance it looked out onto the pediatric pavilion where children with leukemia waited for their chemo. “I mean that’s what I saw every day. It was right in front of me. All the time. My view was of those kids. That kind of reprioritizes your life. I decided that I wanted my work to be about children, and from there it wasn’t far to deciding that it should be children with the diseases that everyone else ignores.”
At the heart of the difficulty in combating malaria, as I learned from Roepe, remains a still unknown and perhaps unknowable mystery of nature. This is where Roepe has trained his sights. “Quinine was the traditional drug used to treat malaria, and then came the much less expensive chloroquine, which the Germans created during World War II. But we still don’t know exactly how chloroquine works,” he told me. “We thought [the parasite] would never be drug resistant, and in fact it wasn’t after six months. Instead it took thirty to forty years.” Chloroquine’s initial advantage over quinine was that it was vastly cheaper, but eventually the parasite evolved to become resistant to both.
The malaria parasite thrives by literally eating the hemoglobin in the red blood cell. What’s left as a result of the metabolic process is heme, a toxic substance. To prevent itself from being poisoned by the heme, the parasite is able to crystallize it and sequester it harmlessly off to the side. Malaria drugs interfere with the parasite’s ability to do this, but no one knows exactly how. “We try lots of different possibilities until we find a drug to which the disease is sensitive,” Roepe explained. “When we find one that works, we go on to solve another problem. We don’t spend a lot of time trying to understand why it works.”
Just as Roepe was entering the field, a consensus was developing that a certain gene in the parasite was the cause of resistance. Experiments to investigate this multi-drug-resistant (MDR) gene took about ten years. Funding was insufficient, and, according to Roepe, “no one was interested . . . except the NIH, the military, and the Brits.” It was Roepe’s experiments that ultimately disproved the theories about an MDR gene. “The idea that one gene could be responsible for resistance is a gross oversimplification,” Roepe said. “There were a lot of people unhappy with me for coming in as a young upstart and making t
his claim. Today everyone agrees with it but some are still unhappy with me. I guess I’ve always been a renegade.”
Though Roepe has dramatically advanced the field’s knowledge, and is on the cusp of being able to help unravel the age-old mystery of how drug resistance develops, he didn’t foresee being able to completely solve the drug-resistance conundrum. “I think of it as staying ahead of the resistance curve,” he told me. “The parasite will continue to mutate and adapt and we will always have to develop new drugs in response. But it used to be very difficult to know which drug to use because it was difficult to know which drug the parasite would resist. Now a blood test can tell us this almost instantly. That gets the cost down.” Which is a critical factor in underdeveloped regions of the world. As Roepe recalled a military corporal in Southeast Asia once telling him, “you’ve gotta make it for 50 cents a dose or you might as well not make it.”
When the existing technology was too limited for Roepe, he invented new technology. When the knowledge in one field of science was insufficient, he collaborated across disciplines, bringing in physicists and molecular biologists. When he concluded that existing diagnostic tools enabling doctors to match medicines to the type of malaria were too time consuming and expensive, he made economics the driving force behind creating a better method.
“With all due respect to Steve Hoffman, a vaccine would be great, but that’s at least ten years away,” said Roepe. “And with 2 million kids dying every year from malaria, that’s 20 million freakin’ kids that will die,” he added, his voice starting to rise. “In my humble opinion the Gates Foundation ought to balance a bit more of its funding to get drugs to these kids now.”
The kind of work Roepe is doing gives malaria drug developers their best chance of keeping pace with the parasite’s relentless ability to evade their attacks. And he put his finger on the classic tension that continues to exist between those who would invest in long-term efforts to actually eradicate the disease, like a vaccine, which may seem impractical and far-fetched, and those who believe that the pressing nature of urgent human needs demands more immediate action. Faced with the reality of finite resources, it does not always seem feasible to do both. But that’s just the kind of failure of imagination that Steve Hoffman has fought to overcome.
