The Imaginations of Unreasonable Men

by Bill Shore

  The pros and cons that Melinda Gates articulated were almost identical to those we’d discussed at Share Our Strength when we had been debating whether to set a goal of ending childhood hunger in America—not reducing it, but ending it. Many of the experts in our community cautioned us about the complexities of measuring our progress and the risk of failure. But as Gates understood in making her remarks, the experts are often expert in what has been, but not in what could be.

  “The world is failing billions of people,” Bill Gates told the World Health Assembly in Geneva in 2005:Rich governments are not fighting some of the world’s most deadly diseases because rich countries don’t have them. The private sector is not developing vaccines and medicines for these diseases, because developing countries can’t buy them. And many developing countries are not doing nearly enough to improve the health of their own people.

  Let’s be frank about this. If these epidemics were raging in the developed world, people with resources would see the suffering and insist that we stop it. But sometimes it seems that the rich world can’t even see the developing world. We rarely make eye contact with the people who are suffering—so we act sometimes as if the people don’t exist and the suffering isn’t happening.22

  In October 2008 I flew to Seattle to check in with the global health experts at the Gates Foundation on the progress of their malaria vaccine initiative. Joe Cerrell, director of global health and advocacy for the foundation, echoed his boss in explaining that, first, markets don’t work for 2 billion of the world’s poorest, and, second, “sheer visibility” is a challenge, in that “the problems are 7,000 miles away and don’t factor in to the psyches of those who could make a difference.” Perhaps most important, the Gates staff had come to learn, as Steve Hoffman and Peter Hotez had, that “the best science is not always the best solution,” in the words of Tom Brewer, senior program officer for infectious disease at the foundation. Sometimes the best science is the science one can afford to scale.

  With the stakes so high, one might expect more effective leadership and coordination among the various malaria experts and activists. But for decades there was very little leadership, because there were few resources and little to lead. Malaria’s victims were too voiceless and invisible to attract funds, talent, or champions to their cause. The fight against malaria was more like a game of whack-a-mole. Each time the parasite was attacked from one direction it popped up in another. There was no one calling the shots.

  By any measure, the battle was too underfunded to be considered a fair fight. A study by the Malaria R&D Alliance, an international coalition of malaria research groups, found that spending on malaria research and development in 2004 amounted to just $323 million, less than 0.3 percent of total health spending worldwide, even though malaria accounted for 3 percent of the global disease burden. 23

  Of that $323 million, $129 million came from the U.S. government. European governments contributed $31 million, and the private sector, $39 million. The nonprofit sector provided 32 percent of the funding, with an investment of $103 million.24

  But even a few hundred million dollars gets spread too thin when it has to stretch across a planet with such large swaths of territory hospitable to mosquitoes and malaria. A 2008 report by the Kenya Medical Research Institute showed that only twenty-four countries received more than $1 per person for each person at risk, and only seven countries received more than $4 per person. The Democratic Republic of the Congo, Côte d’Ivoire, and Pakistan received only 11 cents annually per person at risk. Sixteen countries, including seven of the poorest in Africa and two of the most densely populated at-risk nations (India and Indonesia), received less than 50 cents for each person at risk.25

  It was hardly a scenario for attracting the best and the brightest to the field, stimulating innovation or entrepreneurship, or seeding a new generation of doctors willing to commit to helping the most voiceless and vulnerable people in the world. Tropical medicine had become like a historic landmark in a once trendy neighborhood that time had passed by and that had long since fallen out of fashion. No one looked to move there anymore, and hardly a penny had been spent in ages to spruce things up. Instead, most young medical professionals seemed to be clamoring for lots in the newer subdivisions of Genomic Gardens or on Dermatology Drive.

  Resources remained scarce for decades. Then one day the Bill and Melinda Gates Foundation moved in, made global health a top priority, and began awarding large and numerous financial grants based upon their conviction that something needed to be done. Everything changed. Tropical medicine and neglected diseases were once again fashionable and funded. Scientific enterprises came back to life. Biotech boutiques opened their doors. The activity attracted talent. Labs working on everything from dengue fever and malaria to schistosomiasis and leishmaniasis enjoyed a surge of postdoctoral applicants from around the world.

  In 2005, the Gates Foundation announced that it would make grants of $258 million over five years to support malaria treatment and prevention. The U.S. government was virtually shamed into keeping pace. By 2007, funding for malaria control, including bed nets, improved diagnostic techniques, and drug and vaccine development, had reached $1.5 billion, with 34 percent coming from the U.S. government. Funding from international donors tripled in just three years, going from less than $250 million in 2004 to $701 million in 2007.26

  The Presidents Malaria Initiative (PMI) is led by the U.S. Agency for International Development and is implemented jointly with the Centers for Disease Control and Prevention (CDC). PMI funding has steadily increased, going from $30 million in fiscal year (FY) 2006 to $135 million in FY 2007, $300 million in FY 2008, and $300 million in FY 2009. PMI funding for FY 2010 is expected to reach $500 million. 27

  Though funds devoted to malaria have doubled since 2003, most experts estimate that four times the current amount of funding is necessary to meet the Millennium Development goals of cutting the number of malaria cases in half by 2015. But money is just part of the story. Mark Grabowsky of the Global Fund to Fight AIDS, Tuberculosis and Malaria wrote in a commentary for Nature that “adequate funding for malaria control is an important first step, but unprecedented coordination, planning and operational support will be required to achieve the goals.”28

  Putting up so much money earned the Gates Foundation the right to coordinate, plan, and lead. Sometimes, such influence provokes a resentful backlash. The foundation staff is appropriately sensitive to the fine line between leading and coercing. Foundations can be notoriously heavy handed in influencing the direction and even agenda of their grant recipients, rather than just supporting them. And so lip service is given to the notion that the Gates Foundation is “only” a funder. In a speech in the fall of 2004 at the University of Washington, Bill Gates jokingly referred to the awkward dynamic between grant maker and grant recipients, saying that success in the philanthropic field was much harder to measure than success in his other endeavors. “In business, the market tells you when you’ve failed. In science, your instruments tell you,” Gates said. “In philanthropy, no one tells you. Everyone wants to be your friend.”29

  But the Gates Foundation leads by default as well as by intent. It’s still early to say whether its leadership will be embraced or resisted, but at least the opportunity for leadership has been created. The toughest tests still lie ahead. For now, there have been many beneficiaries, not least of whom is Steve Hoffman, who with Gates funding was able to move his tiny lab from a small strip mall in Rockville to the sprawling manufacturing facility that helped qualify his vaccine for clinical trials.

  CHAPTER 8

  SANARIA HAS ITS DAY IN THE SUN

  The multimillion-dollar effort to eradicate one of the world’s deadliest diseases received a significant but controversial boost yesterday when scientists announced the creation of genetically modified mosquitoes that cannot pass on malaria. . . .

  The strategy is likely to prove contentious as it would require the unprecedented release of tens of
thousands of GM organisms into the wild. But it has raised hopes among scientists, some of whom believe it may be powerful enough to finally bring under control a disease which strikes 300 million people a year and causes more than 1 million deaths, mostly of children in sub-Saharan Africa.

  —Ian Sample, “Malaria: GM Mosquitoes Offer New

  Hope for Millions,” The Guardian, March 20, 2007

  DR. PEDRO ALONSO, FROM THE Hospital Clinic of the University of Barcelona, flew to the October 2007 Gates conference in Seattle, and in front of a large audience of experts, which included Steve Hoffman, announced the release of a report in The Lancet showing that the RTS,S malaria vaccine candidate had proven to be more promising than anyone had expected. International health workers had administered the vaccine along with other routine immunizations to 214 babies in Mozambique in 2007, and the report was claiming that it had cut the rate of malaria infections in the infants by 65 percent. “It is hard to overstate what a major step forward this is,” said Rip Ballou.1 It garnered headlines in the New York Times and worldwide, but the news was quickly overtaken by the inspiring yet controversial challenge from Bill and Melinda Gates at the malaria forum in Seattle.

  Fast on the heels of that news, with some of those who’d been at the Gates event in Seattle heading east via red-eye flights, came a day-long ceremony celebrating the opening of Steve Hoffman’s new facility for the clinical manufacturing of a live, attenuated, sporozoite malaria vaccine, the only one of its kind in the world. It was yet another advance—perhaps the most unlikely of all—in the battle against the world’s most lethal infectious disease for children. (The media coverage itself was revealing—The Times of India, Reuters South Africa, and Australia’s News-Medical.Net all reported it, but not the Washington, New York, Chicago, or Los Angeles papers.)

  Steve Hoffman’s ability to get the most eminent members of the malaria world to the opening of a building long before a viable vaccine had been produced within it was a tribute to his ingenuity and competitiveness. Without sufficient current results that could match RTS,S, Hoffman was selling the promise of the future, and this new facility embodied it.

  The opportunity to invite Bill and Melinda Gates to attend Sanaria’s ribbon cutting had been too great for Hoffman to resist when he was with them in Seattle. With hundreds in attendance at that conference, Hoffman posed a challenging question during the Q&A after Bill Gates spoke. When the chance to ask questions was announced, Hoffman seized it in order to put his fledgling venture on the map.

  “So I ask this pointed question,” recalled Hoffman, telling me about the incident later. “Given the fact that the HIV virus has nine genes and the malaria virus has 5,300 genes, when is their funding going to equal the complexity of the challenge? Gates danced around it just fine. But then at the coffee break, someone comes over to me and says ‘Are you Dr. Hoffman?’ And I say yes. And they say ‘I’m sorry, there’s been a mistake. You’re supposed to be sitting at Mr. Gates’s table!’”

  “So I move over to an empty seat at Gates’s table,” Hoffman told me, “and there I am, on GSK’s big day, the day they make this big announcement, and I’m sitting during the rest of the session with Bill Gates.” Hoffman asked Regina Rabinovich, director of infectious diseases for the Gates Foundation, about inviting the Gateses to the opening, and she said, “We don’t go to building openings. It’s premature. The vaccine hasn’t been proven yet. We’d rather wait to celebrate the results of clinical trials.” Hoffman thought, “I know it’s just a building opening, so I realized that celebrating would be a little controversial, but I have to keep my people going. So I invited them anyhow.”

  Hoffman sent his staff an e-mail that day. It read:Dear Sanarians, I am at the Malaria Forum sponsored by the Bill and Melinda Gates Foundation. There are 250 individuals here from all over the world who are the leaders in the effort to control malaria. These include 4 Ministers of Health, the Director of UNICEF, the Director of NIAID, a British Member of Parliament, etc., etc. Yesterday morning the session started with talks by Bill and Melinda. They were inspiring and enunciated the challenge to everyone in the room that the goal was to eradicate malaria not just control malaria. Few in the room had been willing to embrace this concept even the day before when there was a heated discussion about setting goals beyond control. As you know our website has stated the following for the last 6 months, “Malaria Eradication Through Vaccination.”

  The e-mail continued in the same vein, rallying the troops with new causes for optimism and new reasons to believe that their work would ultimately be vindicated. The truth was more complex. Hoffman had his new space, and he had sat at the Gates table. But he knew full well that was not enough: “[Sanaria had] twenty months’ worth of cash” before it would go negative, he told me.

  Securing grant money is an endless process and is endlessly frustrating. Sanaria’s expansion had been possible thanks almost entirely to the grant of $29.3 million of Gates’s money through PATH Malaria Vaccine Initiative (MVI), but even this grant had once promised to be as much as $80 million. Moreover, grant givers can be very interfering in the eyes of visionary entrepreneurs: “Most of them have never done clinical trials. Yet they are telling me how to design mine,” was how it seemed to Hoffman.

  Nonetheless, the money allowed Hoffman, by August 2007, to complete his state-of-the-art vaccine manufacturing facility in Rockville, Maryland, but progress was not always smooth. For one thing, the MVI wanted to resolve whether Sanaria could continue to contract with Hoffman’s wife’s company, which was called Protein Potential. His wife, Kim Lee, served as vice president of Sanaria, and Steve served as chairman of her firm. The MVI people were concerned about a conflict of interest—or, more likely, the appearance of it. “So I’ve had to spend thousands of dollars on lawyers,” Hoffman told me, in the annoyed tone of one who has experienced the legal profession exclusively as a nuisance.

  Sanaria actually had no choice but to work with Protein Potential. No other company could do what Kim Lee’s could to sterilize and purify the vaccine they had developed. It was a highly specialized technology and perhaps the key to overcoming the regulatory obstacles that the rest of the vaccine community assumed would doom Hoffman’s chances. “I’m astonished that we’ve been able to do this and keep it sterile,” Hoffman said. “I really find that astonishing. . . . That’s all Kim Lee. Her standards are very exacting.” Still, they had to ensure an appropriate way for the transactions to be conducted through a third party.

  It had only been a few months earlier, in March 2007, that I’d visited Hoffman on what he declared to be a “banner day.” On each of the previous occasions I’d visited Sanaria, he had also declared it to be “banner day.” This was either luck, coincidence, or an indication of Steve’s gift at a form of self-promotion that manages to get others to be as invested in and enthused about his work as he is. It may also be an internal motivation strategy. The road to a vaccine is so long and problematic, such a long-odds gamble, that those who succeed are those who find ways to keep going across an inhospitable desert, squeezing enough sustenance out of each small victory and milestone, while those around them drop behind or perish.

  “Last week we actually manufactured the vaccine,” he told me that March. “Right here. Three hundred vials of it. And we had them tested to see if they were safe, sterile, stable. The tests came back today.” Then, speaking slowly for emphasis, he added, “They are safe, sterile, and stable. This is what we need for the preclinical toxicology studies, which will be with rabbits. When those studies come back, we file an Investigational New Drug Application and the FDA has to get back to us within thirty days. Then we go to clinical trials and within six months of putting it into the arms of volunteers, we will know how effective it is.”

  Steve suggested we ride together to the building that would house the new lab. We got in his nine-year-old Jaguar to drive out to Rockville’s Biotech Corridor, just fifteen minutes away. On the highway, to my surprise, the car jolted an
d sputtered, and Steve visibly struggled to keep it moving, pumping the gas pedal, gripping the jerking steering wheel with both hands. It was not what I had expected from a polished and shiny Jaguar. It seemed just a matter of time before we would be stranded along the side of the road. But Steve never made mention of it. He kept up his monologue about a BBC film that had been made about malaria vaccines, as if I thereby might not notice, as if the only thing that could bring the vehicle to a halt was acknowledging its shortcomings. It was not a bad metaphor for Sanaria’s journey so far—an impressive-looking operation that seemed at times to be lurching from start to stutter to almost stop, with a driver who kept his eyes straight ahead, powered by confidence, faith, or the simple conviction that there was nowhere else he’d rather be going.

  Sanaria would have several floors of the building that also housed a few other companies, but it seemed all but abandoned as we toured it. We never saw another human being. This space was previously a lab for another biotech company, and the lab benches and tables were still there, waiting to be torn out. It was at least ten times the space he’d had to work with hitherto, with room for eight dissectors. There were individual offices and large, enclosed areas for manufacturing, including the autoclave, which would sterilize equipment via high-pressured steam; the 14,000-pound irradiation machine; and the insectary. The life sciences supply company Fisher Scientific would store the finished product. It was a professionally designed facility, equipped for the purpose: “The lawyers and advisers really didn’t want us making the vaccine at the other place,” Hoffman said. “They just didn’t think it would look right given the way that stuff was all thrown together.” He would later admit about Sanaria’s first facility: “We couldn’t control the temperature. We couldn’t control the air. We had floods. One time during one of those manufacturing campaigns it got to be 104 degrees outside and the air conditioner froze to the roof. So Bob Thompson, our director of operations, was up there with a blowtorch trying to unfreeze it.”