The Imaginations of Unreasonable Men (11 page)

“Steve’s a smart guy,” Lanar told me. “He used to work right here. But what he’s trying won’t work.”

“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:

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 this 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.

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.