The Imaginations of Unreasonable Men

by Bill Shore

  The battle against malaria was being waged by a relative handful of obscure experts and specialists in research labs, military hospitals, and schools of public health, just as it had been for more than a hundred years. It was the classic “neglected disease”—not on the radar screen of most of the developed world or receiving much support. There were about seventy different vaccines in development, most underfunded, and none instilling confidence.

  Now, less than a decade later, Hoffman was at the beginning of his clinical trials, and GlaxoSmithKline’s researchers were near the end of theirs. Bill and Melinda Gates had declared it the decade of vaccines, and billions of dollars in new funding had been committed. Jay Keasling had contracted with Sanofi-Aventis to mass-produce artemisinin. The Global Fund to Fight AIDS, Tuberculosis and Malaria was reporting the distribution of 108 million bed nets a year. There had been striking increases in public awareness, political will, and consequently, resources, ranging from the World Bank’s increased financial commitment of $200 million to Idol Gives Back, the Emmy Award-winning television show on Fox that engaged celebrities to help raise $45 million for the cause from viewers.

  Most important of all, there had been at least some measurable results, particularly from control strategies such as insecticide spraying and bed nets. The number of African households with at least one bed net increased from 17 percent to 31 percent between 2006 and 2008, and 9 of 45 malaria-endemic countries—including Eritrea, Swaziland, Botswana, Equatorial Guinea, and Zambia—had seen a 50 percent drop in cases, thanks to a tenfold increase in funding for malaria control since 2004.2

  Spurred on by such outcomes, other African countries in 2010 were making unprecedented efforts to achieve universal coverage, hoping to cut malaria mortality in half. For example, Congo and Nigeria, which together accounted for 36 percent of the malaria burden, were mounting the largest net-distribution campaigns in the history of malaria control.3

  No one was debating that a sense of optimism had taken hold. Whether such optimism was warranted, however, remained an open and energetically debated question. In 2009, the World Health Organization reported 243 million cases of malaria and 863,000 deaths attributed to the disease.4

  As a result, not all global health leaders joined in the celebration. Those with long memories had seen misplaced optimism before, sometimes with devastating consequences. Some saw the danger of becoming a victim of one’s own success looming, especially because so much of the success came from methods like using bed nets, which reinforce a narrower, not a more expansive, approach. Bed-net advocates ignore or dismiss vaccine development as a distant ideal. Vaccine developers have little interest in, and rarely advocate for, investing in medicines, a strategy they see as shortsighted compared to developing a vaccine to prevent infection in the first place. This, along with reports of emerging resistance to artemisinin and the belief that even current efforts lack sufficient breadth and ambition, have combined to produce dissenting voices.

  The medical journal The Lancet timed its World Malaria Day editorial to emphasize that “malaria control and elimination via prevention and treatment can only go so far. The risk of serious setbacks is ever present. What is still needed is the only tool that has ever truly conquered any infectious disease: an effective and affordable vaccine. And here, the global malaria community has been too complacent.”5

  On the Friday before World Malaria Day, the Wall Street Journal led with a cautionary tale about the perils facing even the most ambitious vaccine strategies. The front-page story was not about the newly energized global effort to eradicate malaria, but instead about the decades-long struggle to conquer polio and the setbacks that organizations working in the field of global health, including the Gates Foundation, had encountered in their strategy of massive vaccination campaigns. 6 The painful lessons learned may be invaluable to how we think about eradicating not only polio and malaria, but hunger and other persistent challenges as well.

  The Wall Street Journal article documented new polio outbreaks in a number of African countries—Uganda, Mali, Ghana, Kenya—that had been believed to have stopped the disease. Over the past two decades, $8.2 billion has been spent to kill off polio, with the hope that it would soon be eradicated just as smallpox was in 1979. Bill Gates alone spent $700 million to fight polio. Success seemed close. The number of polio cases in 1988, 350,000, decreased to under 1,000 by the year 2000. But in 2009 new outbreaks brought the total back to 1,600 cases. Once polio was ended in some countries, weak health-care systems, poor sanitation, and malnutrition allowed it to return.

  The Wall Street Journal, describing it as “one of the most controversial debates in global health,” framed the debate this way: “Is humanity better served by waging wars on individual diseases, like polio? Or is it better to pursue a broader set of health goals simultaneously—improving hygiene, expanding immunizations, providing clean drinking water—that don’t eliminate any one disease, but might improve the overall health of people in developing countries?”7

  Big donors usually prefer the “vertical” strategy of fighting individual diseases, and advocates are influenced by the preferences of big donors. When a more “horizontal” strategy is pursued, focusing on a broader spectrum of health-related issues, the objectives are often less specifically defined. Dead-lines are often nonexistent, since improvements are likely to take many years longer than in vertical-style projects. And yet the horizontal strategies can be just as important as the vertical ones to long-term success. The Gates Foundation and allied organizations, the Wall Street Journal said, were devising a revamped plan that would represent a major rethinking of strategy acknowledging “that disease-specific wars can succeed only if they also strengthen the overall health systems in poor countries.”8

  It seems an obvious and commonsense insight, but it reverses decades of conventional wisdom that most of the global health community embraced, funded, and acted upon. It also underscores that very different ways of thinking and very different strategies can not only complement each other but be necessary if diseases like malaria and polio are to be drastically reduced or eradicated.

  How could Gates and his colleagues have missed this before now? It’s not that they aren’t smart. Resources were not a primary constraint. Gates has an impressive track record of matching his big bank account with big ideas. No one has ever accused Microsoft’s founder of lacking vision or thinking small. But even Gates suffered a failure of imagination when it came to fighting polio. The enormous financial commitment he made to the disease-specific approach must have seemed like a leap of imagination in and of itself, perhaps the bolder course in the either/or choice described above. But bolder still is the decision to do both, notwithstanding the pressure it creates to generate needed resources, maintain focus, and ensure the ability to measure results. It shows that those fighting diseases as intractable as polio or malaria—or taking on any other task of that size—have to ask whether even their most ambitious efforts lack vision and imagination.

  WHEN MAN AND MOMENT INTERSECT

  Against the backdrop of the millions of lives threatened by the emerging resistance to artemisinin, and a malaria community energized by new funding to support a wide variety of creative experiments, stands the curious figure of Steve Hoffman.

  Doggedly championing what is perhaps the most unconventional approach of all, Hoffman had taken on and refuted every argument—purity, safety, effectiveness, stability, feasibility—for why his vaccine could not work. When he was done, there was nothing left but an immunogen that had demonstrated more than 90 percent effectiveness, and that the FDA had approved for Phase I clinical trials as a vaccine.

  Why Hoffman? What propelled him and his idea past literally thousands of others? What has brought him to the brink of success?

  As is often the case, the answer lies at the intersection of the man and the moment, a combination of his personal qualities and the trends and the times in which he lives.

  Hoffman’s personal qua
lities can be summarized in three words: imagination, entrepreneurship, and leadership. I’ve never heard Hoffman speak in such terms; he only demonstrates and embodies them. The combination of all three is occasionally seen in business or politics, but rarely in science. In Hoffman’s hands, it has proved a potent formula.

  Hoffman’s hard-earned technical successes transformed the perception of his vaccine from preposterous to miraculous. More important, he had the imagination and vision to see each scientific and technological breakthrough not as an end in itself but as the means to a larger end. The time he devoted to science was more than matched by the time he spent coaxing the scientific and philanthropic community up and over Mount Improbable, that Everest-like mountain of skepticism that had prevented them from seeing a potential solution lying long dormant, but nevertheless in front of them all along.

  Art instructors urge aspiring artists not to paint what they think they see or what their minds have conditioned them to see, but what they actually see in front of them. Hoffman championed a similar discipline: peeling away preconceived notions about the drawbacks of a vaccine based on live, attenuated parasites and insisting instead on a notion at the heart of all good science—that the vaccine be judged on the evidence and facts. And like Brother Thomas Bezanson, who never hesitated to break a pot that was good but not good enough, Hoffman steadfastly rejected RTS,S, which he’d even had a hand in creating, and any other vaccine that fell short of the gold standard of nearly 100 percent protection.

  The technical barriers to success were not inconsiderable. When the yield of parasites harvested per mosquito was not to scale, Hoffman and his team figured out how to increase it. When the time came to irradiate the mosquitoes so that each one received the same dose of radiation, he figured out how to do that, too. Hoffman’s wife, Kim Lee, had solved issues of purity and sterility. On and on it went, through years of tedious testing, revision, and refinement.

  Over a decade there were hundreds of such technical challenges. They related to how the vaccine would be created, handled, stored, transported, and delivered, at what temperature, in what material, in compliance with which regulations, and so on. And still there are challenges. How will such a vaccine, once manufactured, actually get to Africa and into the infants and children under five years old, the group that needs it most?

  Skepticism remained, but each technical achievement became a foothold on Mount Improbable, bringing its glittering peak more clearly into view. Hoffman had seen the summit in his mind’s eye; now he had to drag and cajole the whole climbing team that straggled behind him.

  The skepticism was not entirely unwarranted. Hoffman’s assault on the malaria parasite was neither obvious, at first, nor practical. It was fraught with hardship and with hurdles so steep as to be considered unimaginable, and if imagined, then so difficult, complex, expensive, and tedious as to be unacceptable. As Hoffman along with several colleagues wrote in the journal Human Vaccines, the initial insight “was accompanied by an equally universal consensus that it was inconceivable to consider developing an attenuated P. falciparum sporozoite vaccine . . . not due to concern about the potential safety. . . . Rather, it was believed to be impossible to manufacture and administer adequate quantities of aseptic, purified, well-characterized, stable P. falciparum sporozoites that met regulatory and cost of goods requirements.”9

  The doubters were simply holding to conventional wisdom. But for Hoffman, conventional wisdom prevailed only until weighed against the alternative: the disaster of death and destruction inherent in maintaining the status quo. Hoffman insisted, repeatedly, that his vaccine be judged that way: not on its own, but in comparison to the alternatives.

  Many said the beginning of Hoffman’s Phase I clinical trial marked a critical turning point. One tropical disease expert, Michael Good, the director of the Queensland Institute of Medical Research, called the trial a “watershed event” and went on to say it was “the culmination of a remarkable translational research effort by Sanaria.” Many had believed the vaccine would not be able to meet the FDA’s rigorous requirements for safety, sterility, purity, potency, and reproducibility, but Sanaria, said former president of Merck Vaccines, Adel Mahmoud, had “been able to systematically overcome obstacle after obstacle.” Myron Levine from the University of Maryland explained that previous research had never been translated into vaccine development “because the task was considered to be impossible.”10

  These comments underscored a principal ingredient of Hoffman’s success. “Remarkable translational research effort” is scientific jargon for relentless entrepreneurship. The classic hallmark of entrepreneurship is a willingness and ability to adjust, evolve, and adapt, along the lines of Darwin’s explanation of evolution: It is not the smartest or the fastest or even the strongest that survive, but those most able to adapt.

  Hoffman reminds me of one of those robotic floor sweepers or battery-operated kid’s toys that, when running into a wall, simply careens off into another direction. There’s no sign of it being worse for the wear, no matter how many times it bounces back, and eventually it has covered the entire floor.

  Hoffman combines imagination and entrepreneurship with leadership, inspiration, calculation, and strategy, and especially with what the historian Richard Neustadt said characterized effective U.S. presidents, the power to persuade. Neustadt explained that the power to persuade “is more than charm or reasoned argument”; it is enabling others to see why it is in their self-interest to act in a particular way.11

  Just as science, entrepreneurship, and philanthropy evolved, so, too, had Steve Hoffman—from one man with a vision to the leader of an enterprise that has attracted diverse and idealistic talent from around the world as well as funding and the increasing respect of the scientific establishment.

  Hoffman’s entire enterprise was built on a slender but tantalizing experiment: In the 1990s, Hoffman and thirteen volunteers, testing Ruth Nussenzweig’s 1967 work, allowed themselves to be bitten by irradiated, weakened mosquitoes about 1,000 times to simulate a natural immunity. When later “challenged” by being exposed to and bitten by regular infected mosquitoes, thirteen of the fourteen were protected from malaria infection. There had been no injections, no lab-created formula or vaccine, only this crude compression and mimicry of nature’s own methodology. From this one set of results, from a sample size smaller than a Little League team, and an experiment tried once and never repeated, Hoffman parlayed his power to persuade into tens of millions of dollars, international attention, and ultimately FDA approval for trials.

  Hoffman committed himself not just to science but to leadership in a way that embodied the prescription of Warren Bennis, University of Southern California professor of business administration, founding chairman of USC’s Leadership Institute, and author of one of the most influential leadership books of all time, On Becoming a Leader:Limits, constraints and reduced expectations are the conventional prescriptions for our time. True leaders, however, are able to see beyond an anemic zeitgeist in order to sense opportunities that can employ and house a multitude.

  Optimists have a sixth sense for possibilities that realists can’t or won’t see. That gives the optimist the ability to “define reality” for others in a compelling way—which is the first task of a leader, as the author Max Dupree has observed. This is not sentimentalism: It is the essence of creative pragmatism. It is good because it works.12

  For Hoffman this has been a way of thinking and a way of being more influential than any breakthrough or “Eureka moment” in the traditional sense. Hoffman didn’t have a strategy, or a formula to be replicated. Instead he had a mind-set. He came upon the vaccine the way Sherlock Holmes came upon the solution to a mystery: “When you have eliminated the impossible, whatever remains, however improbable, must be the truth.” It would be hard to have a vaccine more improbable than Sanaria’s, but it is the improbable that Hoffman is on his way to proving true.

  Although it will be years before we know the final
results of Sanaria’s clinical trials with certainty, and the ultimate success or failure in overcoming all of the other technical, logistical, political, and economic hurdles to eradicating malaria will remain uncertain for even longer, we at least know more about the ingredients of breakthrough thinking that bring one to the pinnacle of such success. Not everyone who makes it to the base camp of Mt. Everest makes it the rest of the way to the top. But just getting to the base camp is a Herculean task that separates the very few from the very many rest of us. Knowing how they got that far is no guarantee that one can go the whole way, but it’s not a bad place to start.

  Hoffman is far from alone there. Rip Ballou, David Lanar, Pedro Alonso, Victoria Hale, and Peter Hotez have all journeyed heroically. At times they’ve collaborated and at times they’ve competed, but from each other’s successes and failures they have always learned. As a result they have not only advanced their own agendas but also the field of global health, creating hope and inspiring others to tackle problems that affect the most vulnerable and voiceless among us.

  WHAT WE SEEK TO KNOW

  In May 2010, the United Nations hosted a special photographic exhibit called “Malaria: Blood, Sweat and Tears.”13 The photos were taken in Cambodia, Uganda, and Nigeria. They show people who either have the disease or are engaged in fighting malaria in some way—as a community health worker, a guard at a bed-net warehouse, or a pharmacist. Each picture is compelling on its own, but when you consider the group of photos as a whole, and examine common features, you gain a better understanding of what these African people must endure, and that is what makes this photographer’s effort to bear witness so powerful.