At one point in our discussion, Hoffman became animated and went into to another room to get the large laminated malaria life-cycle chart that is the indispensable teaching tool of all malariologists. The illustration is the anatomical outline of a human body from about the shoulder to mid-thigh. It shows a mosquito on the arm and then the rapid flow of parasites through the body, first to the liver, and then bursting out of the liver in a new, more mature cellular form. Now “merozoites,” they head into the red blood cells to do their greatest damage. Hoffman laid the chart down on a table and demonstrated strategy like a four-star general explaining a battlefield map. He leaned over it, pointing out critical areas with broad sweeps of his hand.
Hoffman used terms like “merozoite invasion” and spoke of the parasites’ skill at “evading defenses.” He explained the possible options and strategic choice he had made, dividing the diagram into three sections, surveying the various battle-grounds: the transmission stage, which represents the other part of the parasites’ life cycle as it gets into and out of the mosquito; the liver stage, or pre-erythrocytic stage, meaning before the merozoites get to the red blood cells; and the final stage where the red blood cells are being affected.
Hoffman said he is not that interested in campaigns against the merozoites entering the red blood cells. Nor is he interested in the air war of a transmission vaccine—which is also known as an “altruistic vaccine,” because it
doesn’t help someone already infected but instead protects the rest of the community by blocking transmission of the parasite from one mosquito to another.
Hoffman has chosen instead to target the liver as his Omaha Beach. “This is where we’ve got to stop them: in the pre-erythrocytic stage. If they can’t get out of the liver, they die. The T cells will kill them,” he said, speaking of a natural ally the way General Dwight D. Eisenhower during World War II might have spoken of the Brits.
Years of laboratory reconnaissance have revealed quite clearly how the enemy operates. There are two places where the parasite does its work: One is inside the mosquito, the other is inside human beings. Both represent opportunities to put the enemy out of commission.
JOURNEY TO THE CENTER OF THE MOSQUITO
When a mosquito bites an infected person, it ingests the parasite at an early developmental stage. Once inside the mosquito’s midgut the parasites will develop into what are called “sporozoites,” some of which make their way to the mosquito’s salivary gland. The next time the mosquito bites someone, hundreds of sporozoites will be injected into the new victim.
Here’s how the mosquito pulls it off: A female Anopheles mosquito, hungry for blood, lands on a patch of human skin. Only the female mosquitoes bite, and it’s only because they need the nutrients and protein of a blood meal to be
able to make and lay their eggs. Female mosquitoes mate only once, but they store enough sperm to use throughout their reproductive life.
When it bites, the mosquito probes with a long, needle-thin, tube-like proboscis that actually has four tools inside of it: Two have serrated edges to slice and drill a hole in the donor’s skin, one acts like a hose to inject saliva, and the other is like a straw to draw blood into the mosquito’s body.
The authors of an article in the
Johns Hopkins Public Health
magazine described the mosquito’s actions in vivid terms:
At the end of the proboscis, knife-like stylets move rapidly like electric carving knives to split the skin. She gently jabs at different angles in the hole until she nicks an arteriole that spouts a subcutaneous pool of blood that she can draw from. Exquisitely evolved, the female vampire will squirt into the cut a small amount of saliva full of anticoagulants to prevent the blood from clotting.
Within a couple of minutes, her translucent belly bloats and shifts from waxy gray to cherry red. She sucks a few micrograms of blood—more than her own body weight. . . .
. . . 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
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.