The Imaginations of Unreasonable Men

by Bill Shore

  MOSQUITOES MORE DANGEROUS THAN MORTAR ROUNDS

  Malaria creates the strangest bedfellows. The two most likely victims occupy opposite extremes on humanity’s spectrum: the poorest, weakest, least educated, and most vulnerable children on the planet, on the one hand, and, on the other, the strongest, best-supplied, most magnificently trained, healthiest soldiers in the world, who make up America’s military forces and are often deployed to regions where malaria is endemic. These two groups are different from each other in almost every imaginable way, but they’re both vulnerable to a parasite that doesn’t discriminate.

  Between 300 million and 500 million people are infected with malaria each year. Adults usually survive and, though sick and weakened, develop immunity from its fatal form. While childhood mortality from all causes is decreasing in Africa, malaria mortality is actually increasing. The economic toll is believed to be billions of dollars a year in Africa. Malaria exists in eighty-one countries. Health organizations estimate that up to 5 million people have died of AIDS over the past fifteen years. During the same time period, nearly 50 million have died of malaria.3

  When I traveled to Ethiopia in 2002 on the trip during which I met Alima, and the time before that as well, there was no question about whether I would be protected from malaria, not to mention a variety of other tropical diseases. Though I would be jet-lagged and exposed to the elements, staying in places without insecticide-treated bed nets, and lacking knowledge of the terrain and the local ecosystem, I had access to something far more valuable: a Travelers Clinic just a few blocks from my office in downtown Washington, D.C. And I had the $350—more than twice the average annual income of an Ethiopian—to purchase prophylactic medicines.

  There is nothing out of the ordinary about this if you are from a modern country in the developed world. In fact, what would be extraordinary, even newsworthy, would be if I had returned with malaria. This happens, but it is extremely rare. So why are some of us at minimal risk and others constantly flirting with death from a disease we know how to cure?

  Access to drugs and vaccines is only part of the answer. The rest has to do with access to even the most basic medical care. The United States has approximately one physician for every 500 people. Ethiopia has one for every 36,000. The population of Ethiopia is 70 million. There are more Ethiopian doctors in Chicago than there are in Ethiopia. Because many doctors are based where the population is concentrated, there are many rural areas where the ratio would be much worse than one in 36,000.4

  The first time I visited a field hospital in one of the famine-struck regions of the country, it was an hour before I even realized I was in the “hospital.” It was an open-air tent with about sixty ragged straw mats on the ground, a baby laying listlessly on each one, and their mothers beside them, each mom either trying to get some food, water, or medicine into her child or taking a rare opportunity to sleep herself. The mothers covered most of the duties that we expect of nurses. There was a doctor, but virtually no sign of medical equipment, monitors, or any of the paraphernalia one normally associates with a hospital.

  The doctor’s ability to diagnose was seriously compromised; his ability to treat an illness, once diagnosed, even more so. Comfort was not even a consideration. The likelihood of keeping such a facility supplied with the right drugs—the likelihood of drugs reaching such a remote spot on a regular basis—seemed low. If there was anywhere that the moral, scientific, and economic arguments for a vaccine converged, I thought, it was under such a tent.

  Dr. Denise Doolan, who was scientific director of the malaria program at the U.S. Naval Medical Research Center, has said, “In all conflicts in the past century in malaria endemic areas, malaria has been the leading cause of casualties, exceeding enemy-inflicted casualties in its impact on person days lost from duty.” According to a doctor at the U.S. Army research lab, the disease is considered “the primary factor degrading combat efficiency” in those regions.5

  In a 2005 article published in the Naval War College Review entitled “The Mosquito Can Be More Dangerous Than the Mortar Round,” authors Craig Smith and Arthur Hooper documented why disease and illness will likely generate more casualties than combat during military operations in either Africa or Asia. Data from Vietnam alone showed that only a third of hospital admissions were from combat wounds. Two-thirds were from disease and non-battle injuries.6

  Using the 26th Marine Expeditionary Unit’s insertion into Liberia in 2003 as a case study, the authors reported that 80 of 230 troops experienced symptoms of malaria and that “the outbreak was a blow to combat effectiveness.” Several victims developed cerebral malaria, in which blood vessels carrying blood to the brain became clogged.7

  Military history is rife with such examples. In 1942, the First Marine Division was pulled from combat and sent to Melbourne to recuperate because 10,000 of its 17,000 men were incapacitated by malaria. The disease hit 85 percent among the men holding onto Bataan. As the commander of British forces in Burma during World War II, Field Marshall Archibald Wavell, wrote: “We must be prepared to meet malaria by training as strict and earnest as that against enemy troops. We must be as practiced in our weapons against it as we are with a rifle.”8

  Smith and Hooper concluded that “these realities could easily render a U.S. military force ineffective without a combat engagement ever taking place.”9

  FROM IMMUNE RESPONSE TO VACCINE

  Steve Hoffman and Rip Ballou started out in the mid-1980s as friends, colleagues, and allies committed to developing a malaria vaccine that would protect soldiers and children alike. From very different backgrounds, they had both found their way to military commands in Washington, D.C., at about the same time and the same age.

  Ballou, a fourth-generation army officer born at Fort Campbell, Kentucky, had dropped out of West Point after one year but ended up making a four-year commitment to the army as a way of financing his education at Georgia Tech. He then got his medical degree at Emory. In the early 1980s he began work in tropical diseases at the Walter Reed Army Institute of Research.

  Hoffman had shifted from political science to pre-med during an Ivy League education at the University of Pennsylvania. After getting a medical degree from Cornell he joined the navy to practice tropical medicine and spent four and a half years in Jakarta before returning to the United States in 1984. While there, he worked on severe typhoid fever, and The New England Journal of Medicine article he authored that year set the standard for treating the disease. He considers it his most important contribution to date. For the next sixteen years he would lead the malaria program at the Naval Medical Research Center.

  Before long, Hoffman and Ballou had teamed up to try to build on the most significant breakthrough in malaria-vaccine development of the time, which had come from New York University researchers Ruth Nussenzweig and Jerome Vandenberg.

  In 1967, Nussenzweig, building upon earlier work by Vandenberg, had shown that it was possible to prevent malaria infection in mice by immunizing them with irradiated parasites. Unlike quinine or chloroquine used to treat malaria, irradiated parasites could actually alert and trigger one’s immune system in advance, as vaccines are designed to do, to prevent infection in the first place. But Nussenzweig acknowledged that proving the value of irradiated parasites as an immunogen was quite different from proving that they could serve as an effective vaccine. After all, such parasites could be harvested from only one place—the salivary glands of infected mosquitoes. How could that ever be a reliable supply for the massive quantities needed? And they had been introduced as an immunogen in only one way—through the bites of infected mosquitoes. No one had ever even experimented with introducing such an immunogen into human bodies. Of the many possibilities, at least one could probably be counted out: soldiers, business travelers, tourists, and impoverished children rolling up their sleeves and allowing a swarm of hungry mosquitoes trapped in a canister to feed on their blood.

  Ruth Nussenzweig still recalls that when she first arrived
at NYU, “scientists thought a malaria vaccine was impossible” because the many stages of the parasite’s life cycle made it difficult to target one part for use in a vaccine. The first trials of their vaccines were with volunteer prisoners at a maximum-security facility in Jessup, Maryland. According to the Baltimore Sun, a Baltimore longshoreman who killed a man in a bar fight might have been the first human ever immunized against malaria. But letting malaria-infected mosquitoes that had been exposed to X-rays feed on inmate volunteers was still a long way from a practical vaccine. 10

  In 1980, Ruth Nussenzweig and her husband, Victor, became the first to identify and isolate a protein that coats the malaria parasite. It was called the circumsporozoite protein, or CS protein, and they were also the first to show that it was possible to generate antibodies for an immune response against it.

  Hoffman and Ballou set out together to turn that immune response into a vaccine, and their effort became the basis for a vaccine candidate. The army and navy worked on it together, and it was ultimately adopted by GlaxoSmithKline, funded by the Gates Foundation, and put to one of the largest clinical trials ever conducted in the developing world.

  Today that vaccine is known as RTS,S, and for two decades it was on a rollercoaster ride of small victories followed by dashed expectations.

  FROM COLLABORATORS TO COMPETITORS

  In 1987, when Hoffman was at the Naval Medical Research Institute and Ballou at Walter Reed Army Institute of Research, they were so confident in the vaccine they’d developed together that they vaccinated themselves and then challenged a small group of four other colleagues, who agreed to volunteer. Their confidence was misplaced. Within a few weeks, five of the six became violently ill with malarial fevers, Steve after flying cross-country to give a presentation in San Diego, Rip after running six miles and drinking a beer. Ballou said the ensuing headache felt like “a 9-inch spike through my head.”11

  The vaccine was then refined by combining a protein from a parasite with another from the hepatitis-B virus. It worked in two of eight volunteers exposed to malaria. Then an adjuvant, or chemical additive that boosts the body’s immune response, was included, and the RTS,S vaccine was given the commercial name Mosquirix. A 1996 test at Walter Reed showed its promise. The shot reduced new malaria infections in the first two to three weeks by 86 percent, but after that short period it only reduced infection by 30 to 40 percent. Hoffman and others judged it a good breakthrough—but not good enough.

  Hoffman and Ballou began to diverge in their approaches, and neither had an easy time transforming his vision into reality. Ballou later told Scientific American that “it turns out that mice are very easy to protect, and humans are not.” Hoffman, describing his radical effort to extract the weakened parasites that would be used as the vaccine from the salivary glands of irradiated mosquitoes, told Business 2.0: “It’s not a hard process unless you try to do it.”12

  Back when they’d joined the military, it was the only game in town for working on tropical disease and vaccine development. No one else had the money, the scientific facilities, or the pressing need—represented by half a century of disease-related military casualties from Guadalcanal to Liberia—that would justify such investment. But by 2000, revolutions in molecular biology, biotech, and genomics, along with new sources of philanthropic funding, had changed all that. There were private-sector options for both Hoffman and Ballou that simply hadn’t existed before. They seized them.

  Within two years of each other Hoffman and Ballou left the military and went into the private sector to pursue their efforts. Hoffman joined Craig Venter at Celera in another type of race—to map the human genome and find cures for cancer. Hoffman described Celera as “a company with vision, courage, and a billion dollars in the bank.” While there, he talked Venter into mapping the mosquito genome. When Venter and his board clashed over the direction of the company, Venter left. Hoffman soon left, too.

  Ballou retired from the army in 1999 and spent the next eight years in the vaccine industry, including five years at GlaxoSmithKline Biologicals in Belgium, where he was responsible for the company’s clinical development programs for malaria vaccines. In April 2008, he left GSK to join the Bill and Melinda Gates Foundation as the deputy director for vaccines, infectious diseases development, in the Global Health Division. Ironically, Ballou would be in a position at Gates to influence decisions about funding for Hoffman’s work. In 2009 he returned to GSK.

  Hoffman’s path could not have been more different from Ballou’s. He didn’t join a company but started one, creating Sanaria at his kitchen table. While Ballou was ensconced on GlaxoSmithKline’s vast Belgian campus, tapping into the expertise of thousands of scientists, Hoffman was cobbling together a start-up with his wife Kim Lee and his three sons. Dissatisfied with the efficacy of RTS,S—“That’s not a vaccine that could ever be considered for use in the developed world”—Hoffman returned to the Nussenzweig discovery regarding the potential of the weakened parasite to serve as a vaccine, obsessed with the fact that it actually worked, even if no one could figure out how it could be made.

  At that kitchen table Hoffman set out on a path considered so impractical, so unreasonable, that even the Nussenzweigs held no hope that his goals could be achieved. Build a lab that could breed mosquitoes, and dissect their salivary glands in search of sufficient quantities of parasites to inoculate hundreds of millions of children on the other side of the planet? The question was not what could go wrong but what wouldn’t. Growing sufficient parasites? Harvesting them sterile and pure from the salivary gland, of all places? Keeping this “vaccine” stable and effective as it was transported thousands of miles to Africa or Asia? And delivering it how—by shot? By pill? By the bite of mosquitoes?

  But Hoffman didn’t have a boss or board to stop him, or a bureaucracy to slow him down. For the first time in his career he would report to no one but himself, be accountable to no vision or ambition other than his own.

  Unlike the time he spent working with Venter at Celera, though, this time there was no billion-dollar bankroll. The venture required classic bootstrapping, one small step at a time, each glimmer of progress parlayed into a hopeful headline that would yield more funding and more glimmers.

  Though in the beginning Hoffman and Ballou were more collaborators than competitors, as the stakes grew higher their rivalry grew sharper and ultimately fierce. Tens of millions of dollars had already been invested in and by each scientist. Hundreds of millions of dollars more were on the table. Neither was growing younger. Each had something to prove. Though they were no longer in the military, it was soon hand-to-hand combat all over again.

  Each sought to turn his adversary’s strengths against him and to turn his own weaknesses into assets. In contrast to GlaxoSmithKline’s enormous bureaucracy, Hoffman could be agile, take risks, and work outside of the glare of the spotlight. GSK, on the other hand, could use its size, money, and media machine to maintain momentum even in the face of less-than-compelling results.

  For all of GSK’s enormous advantages in resources, Hoffman maintained one leading edge. Large corporate institutions like GSK are not usually the best places to foster imagination or creativity. As William Deresiewicz, a former Yale professor and a widely published literary critic, cautioned the incoming plebes in a lecture at West Point in October 2009:We have a crisis of leadership in this country, in every institution . . .

  . . . And for too long we have been training leaders who only know how to keep the routine going. Who can answer questions, but don’t know how to ask them. Who can fulfill goals, but don’t know how to set them. Who think about how to get things done, but not whether they’re worth doing in the first place. What we don’t have are leaders.

  What we don’t have, in other words, are thinkers. People who can think for themselves. People who can formulate a new direction: for the country, for a corporation or a college, for the Army—a new way of doing things, a new way of looking at things. People, in other words, with vi
sion.13

  The implication is more than a little unfair to Rip Ballou, a good and dedicated man working with thousands of talented and committed people, and actually saving lives. But though unfair, it is not invalid. Hoffman has a way of looking at the same things everyone else is looking at and seeing something different. I sometimes have wondered how he suffered the hierarchy of the military for so many years, or how they suffered him. But it’s no accident that a man of such imagination, a man for whom good is not good enough, is achieving his greatest success while not part of some bureaucracy, whether military, corporate, or governmental.

  CHAPTER 4

  THE BIO-HAZARD LEVEL 3 STRIP MALL

  Thanks to . . . U.S. and Danish researchers the world might be free of malaria soon. Finding a solution to nip the problem in the bud, the researchers have developed a way to attack the gene . . . [that] helps the malarial parasite to reproduce inside the mosquitoes. . . .

  The scientists believe it to be a major breakthrough, because, if the reproduction of parasites is stopped[,] the spread of malaria via mosquito bite can be checked.

  —Themedguru.com, “Attacking Malaria by Nipping

  It in the Bud—Study,” June 4, 2008

  IN FEBRUARY 2006, WHEN I first made plans to visit Steve Hoffman at Sanaria, I expected to find him in a shiny high-tech complex or an industrial park, perhaps on a sprawling campus. Instead, Mapquest turned up a small strip mall in Rockville, just a few minutes from where I used to live in Silver Spring, Maryland. It was in a neighborhood of nondescript self-storage centers, U-Haul lots, and home-furnishing suppliers.