by Bill Shore
Hale told Nature: “Five years at the FDA taught me one thing in particular: the success of a product depends primarily on the product team. The drug and its qualities are often secondary. There are a good number of average drugs on the market that succeeded because they had ace project teams, that overcame every obstacle.”12
When Victoria Hale delivered a keynote address at the Social Enterprise Conference at the Harvard Business School in 2007, more than four hundred students from the B-School, the Kennedy School, and other nearby colleges filled the Burden Auditorium on a Sunday afternoon, many of them having been inspired by the speakers to consider a career in public service or the nonprofit sector.
Hale spoke quietly, as if presenting the results of academic research, but it was clear from the words she chose, as well as her track record since 2000, that a passion, perhaps even an anger, fuels her work. She again used the slide presentation to show the faces of the poorest of the poor around the world, particularly in the Indian state of Bihar. “This is the twenty-first century. Why does that happen?” she asked softly, almost as if addressing herself.
Hale told the students why she started the Institute for OneWorld Health:These people don’t need the same medicines we do. There is a problem with how we make medicines. Medicines are miracles. There is an incredible beauty and power to them. In 2000 I began pulling together scattered ideas based on both my pride in the industry and my shame that we hadn’t figured out how to make medicines for all. We went to India first because we knew we could have success early on. The size and scope of the success is less important than that it be a success. So as we adopted the mission of making safe, effective, and affordable drugs, we wanted to develop an organization that would show the industry a new way of working.
The increased interest in so-called “neglected diseases,” fueled by international politics as well as the massive financial commitment of the Gates Foundation, gave Hale and her organization the perfect wave to ride.
Hale’s political savvy and practical side came through in the talk, too:Mainly, we need to engage the pharmaceutical industry. If we don’t it is a missed opportunity and we won’t be all that we can be. The industry does not know who the poorest people are and we can’t expect them to know what needs to be done. But the carrot is more powerful than the stick and we must ask: What is it you need in order to engage? And also, What are you afraid of? Corporations want to do well and good and we should respect their individual capacity and potential. Don’t presume you know the answers. Ask! And balance patience with persistence because it always takes longer than you hope or dream.
She concluded by urging the audience members to “trust the universe. If your intentions are good, the universe brings you what you need.”13
“HOOKWORM HAS ONLY PETER HOTEZ”
If the development of the malaria vaccine—and the trials and tribulations of Hoffman, Keasling, and Hale—were the only story of its kind, it would still be interesting and instructive. But the nature of vaccine development for those most vulnerable and voiceless, as viewed through the long tunnel of time and shaped by the lack of markets, virtually creates an ecosystem: It’s an ecosystem that serves as a breeding ground for the imaginations of unreasonable men. The life and work of Peter Hotez, who has also devoted a long career to pursuing a vaccine, though for a different disease, demonstrates the broad applicability of the lessons we’ve learned so far. He has worked against the same long odds, and the entrepreneurial strategies and qualities of character required for success were also the same.
Hookworm is a debilitating parasitic disease that afflicts more than half a billion of the world’s poorest children with worms. These worms, using their teeth, adhere to the inside of their victims’ small intestines, tearing away at blood vessels and feeding on hemorrhaging blood. You do not want hookworm.
Some 44 million pregnant women around the world become infected with hookworm annually and deliver babies of low birth weight as a result. These pregnancies are associated with higher than normal infant and maternal mortality. And that’s not all, for the hookworm has no particular preference for pregnant women: Overall, 740 million people a year are afflicted with this blood-sucking intestinal parasite.14
Of course, none of them will be in the United States. Like schistosomiasis and lymphatic filariasi, hookworm is a neglected tropical disease whose prevalence and persistence is related as much to economic conditions as to medical conditions.
For kids, hookworm, though not typically fatal, means stunted height and weight as well as suppressed IQ and cognition. “There are periods in life when one is wormier than other periods, and peak period of worminess is age three or four through age fifteen,” explained Hotez when I visited him at his office at George Washington University in September 2007. “In rural villages in Guatemala, or any rural village in Central America, for that matter, 100 percent of the kids will be infected. When you are feeding a hungry child, you are feeding the worms first.” Hotez is president of the Sabin Vaccine Institute, where he founded the Human Hookworm Vaccine Initiative, and he also serves as Distinguished Research Professor and Walter G. Ross Professor as well as chair of the Department of Microbiology, Immunology, and Tropical Medicine at George Washington University.
Hotez is also the only scientist in the world who is seriously trying to develop a hookworm vaccine. Despite how widespread it is, hookworm infection has received very little attention in the scientific community, and as a result, hookworm vaccine development is not only demanding but lonely work. There is not one paper in the literature that has been written on this leading cause of growth retardation. “Some diseases have Bono or Angelina Jolie as their champions. But hookworm has only Peter Hotez,” said Hotez, underscoring the obscurity under which he labors.
Malaria vaccine researchers are competing fiercely to get to market with the first effective vaccine. Approaches vary substantially in terms of the science involved. Rival researchers are polite but mostly dismissive of one another. Still, they constitute a fraternity of sorts, often reconnecting at conferences and seminars, sharing data, and debating the latest developments. Likewise for research in AIDS and many other diseases. But for Hotez, there are no rivals, and no competing vaccine development project: “No, just me,” he told me when I asked.
Hotez’s grey cinderblock office at George Washington University reinforces his isolation. The phone doesn’t ring all that often. When we toured the lab we met only two other technicians, working alone in two small rooms down the hall.
For many years Hotez scraped by with almost no support. “Neglected diseases, neglected scientists,” he said with a grin. He delved into the reasons that hookworm is neglected. “First of all, it doesn’t kill. It is chronic, and debilitating and disfiguring, but many of the neglected diseases don’t kill and so they don’t rank high in rankings of factors that cause mortality.”
Eventually the Gates Foundation came through with two multimillion-dollar grants. “I don’t think they are all that interested in hookworm,” Hotez confided, “but they are interested in the model we’ve developed of technology transfer to what we call Innovative Developing Countries (IDCs), like Brazil, China, India, and others.”
In an interview for the Department of State’s electronic journal (America.gov), Hotez explained:Product Development Partnerships . . . will actually include what we call public sector vaccine manufacturers in developing countries. . . .
In Washington, D.C., we’ve been able to make pilot-scale amounts of vaccine for early-phase clinical testing, which is underway in Brazil. The problem is the amount we can make in our laboratories through the PDP here in Washington is limited, and certainly not enough to vaccinate all of Brazil or all of the Americas.
So we’ve now partnered with an organization known as Instituto Butantan, which makes 86 percent of the vaccines for Brazil. . . . They’re coming up here; we’re going down there and transferring our technology so that they can do the scale of production for all of th
e Americas.15
As if to underscore how far he’s come, he chuckled: “I even have a hookworm movie.” He wasn’t kidding: He turned to his computer to call up a video taken during a routine colonoscopy that included footage of a hookworm at work. We watched a five-minute excerpt of it together.
Hotez seems to have been destined for this work. As a thirteen-year-old in 1971 he had on his bedside table a volume of Manson’s Tropical Diseases, which, through twenty-one editions since 1898, has been considered the bible of tropical medicine for both clinicians and researchers.
Upon his enrollment at Rockefeller University he was told that Rockefeller’s students were “supposed to do remarkable things.” He took the words to heart. When he read a famous 1962 paper by parasitologist Norman Stoll describing hookworm as “the great infection of mankind,” his course was set.
In a lecture in 2006 at the University of Georgia, Hotez described the long process of making a vaccine, beginning first with dog hookworm. It required one to collect the necessary ingredient of worm spit, which, because you can’t get enough of it from the worms themselves, means turning to genetic engineering. “It took twenty-five years of work to develop a viable strategy for this disease—and that was the easy part!” Hotez recalled. Hotez emphasized that there was essentially no way to create a company to manufacture the vaccine without losing money, describing the project as “the biomedical equivalent of the Broadway play, the Producers—an intentional flop—a guaranteed money-losing enterprise.” But he also cited Gandhi’s aphorism that “no movement ever stops for lack of funds,” a telling point that revealed something of what makes Hotez tick. 16
Despite the idealism that became evident at moments like this, Hotez is nothing if not practical. One vaccine, using a recombinant version of an enzyme, proved effective, but it was costly and difficult to manufacture in bulk, so Hotez devoted his energy to developing a different vaccine. If his ultimate objective is to save lives, he does not have the luxury of just developing an effective vaccine for hookworm, as difficult as that is, but must develop a different vaccine, one that is effective but can be delivered for less than $1 a dose.
“If you can’t make it cheaply, you might as well not make it at all,” Hotez told The Scientist. “We have to build into our design process the ability to deliver this vaccine at less than $1 a dose.”17 This provocative assertion has obvious implications for global health science and medicine. It also suggests a different way of approaching social science. It means at least two things.
First, if you contract a disease in a developed country and your prayers are answered by a cure being discovered, you will get that cure and you will live. But if you contract a potentially fatal disease in a developing country, the discovery of a cure does not necessarily answer your prayers, because there may be no economic way to get that cure to you, even if, by not getting it, you will die.
Second, because the life and death stakes are so explicit and unambiguous when it comes to neglected tropical diseases, vaccine developers must build the economics of manufacture and distribution into their work from the beginning. Consider what is being asked of them. No one expects university economists to know how to isolate protein molecules in lab flasks to determine which ones trigger immune reactions and might be candidates for a vaccine. But doctors who are able to do just that in their labs must also master the rigors of international economics if they want to see their efforts to prevent disease come to fruition.
Businesses face this issue head-on every day. So must the nonprofit sector.
I’ve never heard the term “gross margin” raised in a nonprofit context, although clearly that is what Hotez is getting at when he says of his vaccine efforts: “If you can’t make it cheaply, you might as well not make it at all.” This is not a new principle, or a very complicated one, but neither is it widely appreciated or subscribed to in the social sector.
If one accepts that there is a moral obligation to share our strengths and intellectual gifts to develop solutions to human need, then the moral obligation may be even greater to ensure that such solutions, including vaccines and other preventive measures, are not accessible only to the privileged few.
Economic laws and market forces may be morally neutral, but our willingness and discipline to embrace and marry them to social science represents a choice. It is a choice that we have yet to make and take full advantage.
Most vaccine developers devote their entire lives to creating and testing a vaccine without ever seeing their work finished. Hotez is no different. Now at the pinnacle of his profession, he has been working on hookworm since medical school. As complex as the scientific challenges are, the economic challenges may be even greater. “The hepatitis B vaccine started at $150 a dose,” Hotez told me. “It took thirty years before it penetrated the population.”
But what interests me most about Hotez is not only the science of what he is doing, and the economics of it, but also the determined and sophisticated effort to build political will where it does not exist, and to do so by projecting a voice where there has been silence.
There are 540 million children, some halfway around the world and many here in our own hemisphere, whose intestines are literally crawling with blood-sucking worms. There are tens of thousands of doctors around the United States and the globe, but there is only one who devotes all of his waking hours to doing something about hookworm.
In an article in the prestigious New England Journal of Medicine, Hotez and some of his colleagues attempted to combat a critical notion that contributes to the plight of neglected diseases. Scientists know that more people are dying from HIV/AIDS, malaria, and diarrheal diseases than are dying from hookworm and some of the other tropical diseases, and they conclude that the more fatal illnesses must be given greater priority. As a result, considerably more talent and money go into those endeavors. But by adopting a different metric, one of “disability adjusted life years,” or “DALYs,” Hotez’s team said, the neglected tropical diseases can be shown to constitute large burdens on the health and economic development of low-income countries. Indeed, in terms of DALYs, the neglected diseases rank closely with the better known malaria and tuberculosis. The obvious conclusion: Some of that talent, and money, needs to be going toward combating them.18
THE BILL AND MELINDA GATES FOUNDATION
History has traumatized and scarred the malaria community. Several times over the past fifty years it was believed that the world was on the verge of eradicating malaria. The result of premature celebrations was a decrease in focus, funding, and research, and soon a dramatic increase in the prevalence of the disease. Too often the malaria parasite has been underestimated. Discussion of eradication has been seen as somewhere between naïve and recklessly dangerous. Melinda Gates changed all that.
On October 17, 2007, the Bill and Melinda Gates Foundation hosted a three-day forum in Seattle on malaria, bringing in prominent experts from around the globe. Melinda gave the opening address. Her speech was candid and courageous, passionate and provocative. Historians may look back on it as a pivotal moment. After recounting some of the history of the disease and the way it has plagued people around the world, she said:We wouldn’t let it happen here. We shouldn’t let it happen anywhere.
But over the course of the last century, malaria changed from a disease that afflicted a broad range of countries to a disease that affected only poor countries. It changed from a celebrated cause of our scientists and politicians to a source of suffering that the rich world was willing to accept and the poor world was helpless to prevent. . . .
Bill and I believe that . . . advances in science and medicine, your promising research, and the rising concern of people around the world represent an historic opportunity not just to treat malaria or to control it—but to chart a long-term course to eradicate it.19
Anticipating the concern of those in the audience with far more expertise than her, she added:We know that the word “eradication” is troubling to many people wit
h deep knowledge of malaria. It’s an . . . audacious goal. . . .
. . . But to aspire to anything less is just far too timid a goal for the age we’re in. It’s a waste of the world’s talent and intelligence, and it’s wrong and unfair to the people who are suffering from this disease.
The goal of eradicating malaria has the power to create great expectations, grand efforts, and record funding. When you ask people to donate time and money to save lives, they can be very generous. When you ask them to give time and money to eradicate a disease, their generosity can multiply. Those are the benefits. They are also the risks. If high energy and high expectations don’t lead to success—it saps money and morale. People give up. Governments, foundations, and corporations cut their funding, malaria surges back—and gains can be quickly wiped out.20
Gates gave three specific reasons why we should embrace the goal of eradication. The first one was that it was the ethical thing to do. “Every life has equal worth,” she stated. The second was economic: “If we plan only to control malaria, we will never eradicate it. That means we will keep bearing forever the human costs of malaria, even as we keep paying forever the financial costs of trying to treat and control it.” The third was epidemiological: “Without eradication, we will continuously adapt our strategies to the parasite and the parasite will continuously adapt to us—in a back-and-forth battle that will never end.”21
Both Melinda and Bill Gates made the case that with enough time we could develop the partnerships, political will, and scientific breakthroughs necessary to eradicate malaria. It would take relentless research, coordination, and especially long-term commitment. And eradication would require intensifying efforts as fewer and fewer people were infected, which may sound counterintuitive but is true. Political will and funding diminish when the mortality is reduced.