The Imaginations of Unreasonable Men

by Bill Shore

  A CLUB MED FOR BUGS

  The Bloomberg School of Public Health on the Johns Hopkins University campus in Baltimore is home to one of the world’s most sophisticated insectaries. It is not some sort of showcase for insects, however, with exotic, winged creatures buzzing and flying about. Instead, it exists for a sole purpose: breeding mosquitoes for laboratory research. And when you first pull open the heavy door and walk in, it is so quiet and still that you get the misleading impression that nothing is going on.

  The lab at the school’s Malaria Research Institute actually includes seven separate insectaries producing thousands of mosquitoes a week. Each insectary is accessed through a large steel door that looks like the door of a walk-in freezer—except that the insectaries are kept warm inside and at 80 percent humidity, to recreate the climate in which mosquitoes breed. A computer controls the lighting, which mimics sunrise and sunset. Insectary mosquitoes are fed their favorite foods and encouraged to mate, and the weather is perfect. It is Club Med for bugs.

  Johns Hopkins built the lab when it launched the Malaria Research Institute in 2001. (The school also established a site in Zambia’s Southern Province for field research.) The staff, to a person, harbors an ardor for their work that may seem unusual to outsiders. “A flagellating protozoon is very, very beautiful,” said one professor, who also works on sleeping sickness caused by Trypanosome parasites.

  Another, David Sullivan, is an assistant professor of molecular microbiology and immunology and has been working to develop a simpler diagnostic for malaria that would not require drawing blood. When I asked him why he became so interested in malaria, he responded, “What I don’t understand is why everyone else isn’t interested in malaria. I realized it was the one thing I never minded waking up at two o’clock in the morning for, to run down to the lab, to check on an experiment.”

  The Bloomberg School of Public Health is the largest school of public health in the world. Philanthropic generosity enabled it to create a lab second to none. “This is luxury as far as labs go,” explained Marcelo Jacobs-Lorena, a professor of molecular biology who was lured away from a twenty-six-year career at Case Western Reserve. He smiled broadly as we surveyed a long rectangular room of work benches, microscopes, computers, and shelves crammed full with beakers, bottles, and test tubes. Several of his students were at work, and as modern as this lab may be, they were still doing science as good science has always been done, patiently extracting liquid from a vial, mixing it, observing, and recording results.

  Like many others at the same senior stage of their careers, Jacobs-Lorena has found that his administrative and grant-writing responsibilities keep him from conducting experiments himself. But he lit up when we walked into the lab and clearly enjoyed telling me about the work that was underway there. He began by showing me how the researchers put anesthetized mice on top of the mosquitoes’ wire-mesh cages so that the female mosquitoes could take the blood meals they required for the protein needed to lay eggs.

  The eggs are collected on a thin, soft pad and then placed in an uncovered white tray filled with water, where they lay until they hatch as larvae. Tray is stacked upon tray in a large metal rack, like cookie sheets at the bakery. Dark specks float near the surface or cling to one side. The larvae are fed on pellets of cat food that become bloated and float in the liquid, and then the larvae become pupae. Near the end of their ten-day journey to adulthood, a cloth is placed over the tray so they won’t be able to fly away. The mosquitoes are then vacuumed into another cage where they await the microscope or the dissecting blade of a student or post-doc. Their life span of thirty days lies ahead.

  There are elaborate precautions to keep the mosquitoes confined to the insectary. In each room there was a bug zapper, a lighted blue tube reminiscent of the contraptions I’d encountered in Hoffman’s offices. At this lab, however, there was a net affixed underneath each tube. While Jacobs-Lorena was talking, I noticed with surprise a mosquito zipping around my head, and instinctively, I swatted at it. “There’s always one that seems to get out,” Jacobs-Lorena said, more with amusement than alarm. Every wall contained posters with emergency procedures and phone numbers to call should there be any kind of accident.

  As we entered the special insectary, which is treated as if it were biohazard level 3, he explained that this was where they dealt with the malaria-causing Plasmodium falciparum parasite. Because only female mosquitoes bite and spread malaria, the males are useless to the lab and must be separated out. I asked Jacobs-Lorena how they could tell them apart. He said to just take a look. To my eyes they were blurry tiny black bugs, no larger than a sprinkle on a cup-cake, and indistinguishable from each other. But once he pointed out that the males were long and slender and the females were thicker, with a bulge in the middle, I was able to notice the difference even in the small specks clinging to the containers. “Cold knocks them out and makes them lie very still, so we basically make them cold and then put them on the lab bench and separate the males and females by hand,” he told me. It’s a strange labor of love.

  After that, they are injected by a fine needle with foreign genes in an effort to make them incapable of transmitting parasites. The goal of Jacobs-Lorena’s lab, and his work since 1982, has been the development of a transmission-blocking vaccine. His experiments are designed to determine whether mosquitoes can be genetically modified to interfere with the parasite’s invasion of its midgut and salivary gland. It is in the midgut that the sexual form of the parasite develops, and in the salivary gland that it waits on deck to infect the next human that is bitten. Unlike Hoffman’s vaccine, Jacobs-Lorena’s would not attack the parasite in the liver or anywhere else in the human body; it would instead make it impossible for the parasite to travel by mosquito, and therefore unable to infect humans. Think of it as a genetic modification that takes away the parasite’s car keys.

  To get into the mosquito’s midgut or salivary gland, the parasite must cross through a membrane called the epithelium . Not much is known about how it actually does so, but it’s more complicated than boring right through and in. Jacobs-Lorena described it as more like a key turning a lock; getting the combination just right depends on the molecules found on the surface. Making adjustments to those molecules to prevent entry is what Jacobs-Lorena’s work has been about. It is criticized by some who say he is working to protect mosquitoes from infection, rather than people, but of course, if mosquitoes weren’t infected, people wouldn’t be either.

  In 2000, Jacobs-Lorena pointed out in Parisitology Today that “among the five most deadly infectious diseases (acute lower respiratory infection, TB, cholera, AIDS and malaria) only malaria requires a vector”—or channel (in other words, the mosquito)—“for transmission. In the past, campaigns to control mosquito populations have resulted in dramatic decreases of malaria incidence. However, insecticide resistance and environmental damage quickly reversed early successes and now complicate vector control.”6 As a result, techniques such as manipulation of vectorial capacity—meaning manipulation of the molecules inside a mosquito—are now being considered.

  Jacobs-Lorena acknowledges that his is just one of many competing approaches to controlling malaria, and he knows it has its detractors. But in many ways each of his competitors is in the same boat, facing the same dilemma. Searching for more and more obscure clues, and testing theories that seem more and more eccentric, each has his own hypothesis, one in which he has invested his time, talent, and reputation. And each keeps a wary eye on the progress of his peers.

  Just down the hall from Jacobs-Lorena is the laboratory of Nirbhay Kumar, who came down with malaria as a young man studying for his Ph.D. in New Delhi in 1976. He had always planned “to go back to India and do good science there,” but then a mentor persuaded him of the contribution that could be made on malaria if he stayed in the United States. He is now coming up on his twentieth year at Johns Hopkins.

  Kumar has been working on a vaccine to prevent transmission by mosquitoes, but in
his case, it would be by blocking the sexual development of the parasite within the mosquito. In this way Hopkins has carved out a research niche for itself.

  Kumar explained why he has chosen to work on disabling the parasite: “There are only three variables for researchers to attempt to control: the mosquitoes, the parasites, or the people. You don’t want to eliminate the mosquito. They play other roles in nature that we need. And you don’t want to eliminate people. That leaves the parasite.”

  If Steve Hoffman’s approach is akin to an army general seeking to contain the enemy on the battlefield of the liver where it will be trapped and perish, Kumar and Jacobs-Lorena are focusing on disabling the enemy’s air force, or at least the air force’s munitions capability. Mosquitoes are the aircraft, delivering their deadly payloads with awesome precision. It’s not the vehicle that the does the damage, but what it carries. And if the vehicles can be modified so the munitions are disarmed before they are released, then we will have nothing to fear.

  There are many other approaches being developed as well. In addition to the thirty-five different malaria vaccine development efforts being monitored by the World Health Organization, there are also researchers seeking to find curative drugs, efforts to distribute insecticide-treated bed nets, and other means of fighting malaria. There are two reasons for this vast variety of efforts and approaches.

  First is the very complexity of the parasite’s development and life cycle and the many moments of potential vulnerability that scientists see as targets to strike. As it bodysurfs blood from one human victim through the mosquito to the next human victim, the parasite morphs and differentiates into six completely different forms. It goes through fertilization and then invades various organs and cells.

  Different efforts to combat the disease are aimed at different moments in this cycle, but if we are to prevail, we may eventually have to fight the parasite at every point. The paristologists have essentially adapted Winston Churchill’s famous World War II exhortation: “We shall fight on the beaches, we shall fight on the landing grounds, we shall fight in the fields and in the streets, we shall fight in the hills.”

  As Kumar put it, “we have a problem of multiplicity.” Researchers must confront multiple species of the parasite and multiple strains of each species. The parasite itself has multiple life-cycle stages, invades multiple strains of the mosquito, and exists across multiple epidemiological areas. And most challenging of all is that there are multiple immune responses. Kumar’s colleague David Sullivan captured the daunting challenge when he told me that any vaccine developed “has to be better than nature.”

  Second, because the Plasmodium parasite has evaded or defeated every effort to destroy it, scientists have been forced to pursue increasingly radical, seemingly unrealistic options. All of the most logical ideas have already been tried, and they have failed. What remains are the less logical ones, certainly the less obvious ones.

  All the researchers I met acknowledged being sobered by the experiences of their predecessors. They live with the reality that their efforts are only one piece of the puzzle, with success ultimately being dependent upon factors beyond their control—such as, for example, government and public policy.

  Teresa Shapiro, professor of clinical pharmacology at Hopkins, explained her job to me as “developing the tools. That’s what I have to keep my focus on.” She noted that “success in fighting malaria has waxed and waned over the years, often set back somewhere because of the loss of political infrastructure.” “If politicians and government officials decide they want to deal with malaria,” she said, “my job is to make sure the tools are available. It’s about a lot more than whether we come up with an affordable vaccine. As Jean Genet said at the World Health Organization, ‘even free is too expensive,’ because the costs are in distributing it.”

  “VACCINE MAKERS, LIKE OIL MEN AND GOLD DIGGERS, NEVER STOP DREAMING”

  In the fall of 2006 I drove with some trepidation out to Rockville to reconnect with Steve Hoffman. The last time I had seen him, he’d been so stressed about his biotech business running low on funds that he had worried about having to shut down Sanaria’s operations. I had been checking the company’s website often, and there hadn’t been an addition to it in months. No new press releases, either. Nothing surfaced through a Google search that I hadn’t seen before. Most unusual, there were no new papers written by Hoffman, who has always been one of the most prolific authors in the field of malaria research and tropical medicine. He had spoken of a desire to have a new facility, but his ability to afford one would depend on receiving a major grant. I was worried.

  I didn’t think of Hoffman as someone who gave up easily. Quite the opposite. He is fiercely competitive and proud. Maybe sounding the alarm about finances was just his way of calling the bluff of a prospective donor. Perhaps he’d built in a financial cushion and there was really nothing to worry about.

  Although Hoffman had experience raising funds and managing a department in the navy, he had never run a business, and he had no financial training. For the most part, his career had been lived safely in the confines of enormous, well-funded institutions like the U.S. Navy and Craig Ventner’s Celera. It was usually someone else’s job to worry about the money, meet payroll, manage staff. All Hoffman ever had to do was think about the science, design experiments, and publish research results. Considering that everyone else I’d talked to was skeptical that Hoffman’s vaccine, based on building an assembly line for dissecting mosquito salivary glands, was highly impractical, I started to wonder if he and the lab he’d cobbled together might disappear without a trace.

  Science is all about trial and error, advances and setbacks, and meticulous preparation dedicated to discovering the needle in the haystack. It makes the lab a fascinating and exciting place, but the rollercoaster ride takes a toll on the human beings who perform the experiments. Emotions inevitably seep into even the most sterile labs. Disappointment, anxiety, and fear can never be distilled out completely. I’d detected trace elements of them in Hoffman—mostly in some worried comments he’d made about Sanaria’s precarious finances—and wondered how he’d respond.

  When I got to his office, he was on the phone with a scientist in Colombia. I sat a few minutes looking at some medical journals and admiring his artwork. His walls were covered with more African sculptures and photos than I remembered from previous visits. The place had much more of a “lived in” feel to it. Since I was sifting for evidence that he and Sanaria were here to stay, I seized on this as a good sign. It turns out that I didn’t have to search much farther.

  After concluding his call, Steve stood up and came over to the small round conference table where I was sitting. For the first time since I’d met him, his smile seemed more natural than forced. I asked for an update on where he was now with funding, toxicity trials, production schedules, and the new facility he planned to build.

  “July and August were the worst two months of my professional life,” he began, but with the grin of a man reporting on his own eventual triumph. “Waking up at four in the morning, with that pit in the stomach over whether we were going to go negative, whether we’d have to stop operations. I’ll never let myself get in that position again.”

  Although it was only a fraction of what he needed, the Malaria Vaccine Initiative (MVI) had come through in July with bridge funding: $534,000, and then an additional $200,000—enough to keep the operation going. MVI was created by a Seattle-based organization called PATH that was started in 1977 and sought to advance technology to improve health. MVI was funded by Bill Gates to identify the most promising vaccine candidates, accelerate their development, and ensure eventual licensing and accessibility in the developing countries where they were most needed. They currently fund ten separate vaccine-development efforts around the world.

  And then Hoffman received the best news he’d heard in a long time. “On August 11, while my family and I were vacationing in Alaska’s Denali National Park, I received wor
d that $29.3 million in Gates Foundation money would be granted through MVI,” he said. “We toasted each other over the phone, celebrated, the whole thing, and then a week later they came back and said there were problems with the details of how the grant had been written and we had to go back and start working on it again.”

  The funding eventually came through: “It took a lot of work,” Hoffman said, “but the Gates funding changed everything. It’s not just a matter of being grateful. Many of us would not be doing what we are doing today if not for the Gates Foundation.” The funding would enable him to build a vaccine manufacturing facility and keep going for at least three more years.

  “But now that we’ve got the funding I’ve actually had a kind of postpartum depression, just some feeling of letdown after all of that time,” Hoffman told me, recounting recent experiences:We presented our work at the American Society of Tropical Medicine and Hygiene conference in Atlanta. Our family had been in Singapore with Ben and Seth, who were competing in the World Kung Fu Championship, and then Alaska. So I was jet lagged. I also picked up some viral infection. I’ve been at every ASTMH conference since 1978 and there were 2,500 participants at this year’s, and I know everyone, but I ended up having dinner alone and then going to my room to rent a movie. I had some weird kind of depression now that the money had come through.