The Imaginations of Unreasonable Men

by Bill Shore

  Hoffman did his residency in family medicine at the University of California-San Diego and practiced there from 1975 to 1978. He spent 1979-1980 establishing the Tropical Medicine and Travelers Clinic there.

  But practicing tropical medicine in the United States made him feel “like a fake tropical medicine doc,” he told me. “So after all of the years of antiwar protest and all the rest, I cut my hair and joined the navy so that I could go to their research station in Indonesia and study malaria.” In April 1980 he went to what is known as NAMRU-2, the Naval Medical Research Unit Two, an infectious disease research facility established in Guam in 1943 by the Rockefeller Foundation and eventually relocated to Jakarta, Indonesia. Its primary function has always been to study infectious diseases of military significance because they might threaten mission readiness.

  Within forty-eight hours of his arrival in Jakarta, Hoffman was treating patients with typhoid. In ten weeks he saw seventy such patients, and 18 percent of them died. As he told the American Society of Tropical Medicine and Hygiene, “I had been taught . . . that the mortality rate for Typhoid had been dropped to less than 1%, and I was appropriately horrified, wondering what we were doing wrong. It was clear that there was a major disconnect between what I had been taught about treatment of typhoid, what I as a well-trained physician could do for a patient with severe typhoid, and the outcomes for hundreds of patients in that hospital.”9

  Hoffman spent five years there, from 1980 through 1984. While working on typhoid fever, malaria, cholera, and dengue fever, Hoffman had the experience of every doctor who has practiced there: “countless children died in my arms.” He and his colleagues experimented with different approaches until settling on the use of a high dose of a drug called dexamethasone. In 1984 they published a study about it in the New England Journal of Medicine, and it became the new standard for treating severe typhoid. By the time he left Jakarta, the fatality rate for typhoid had dropped to 1 percent.

  After that he came back to the United States to join the navy’s malaria vaccine development unit in the Maryland suburbs of Washington, D.C., and ultimately to head the malaria program. He also found a way to stay close to patients who could not afford health care, working in the emergency room of Providence Hospital, a community hospital chartered in 1841 by President Abraham Lincoln in what is now one of Washington’s poorest neighborhoods.

  Hoffman’s naval career totaled twenty-one years. Having initiated the Department of Defense’s Plasmodium genome sequencing effort in 1995, he ultimately left to work at Celera. Meanwhile, he became president of the American Society for Tropical Medicine. It was during this time that he wrote most of his 350 scientific papers, while also obtaining numerous patents.

  Along the way he won every professional distinction possible, including the Bailey K. Ashford Medal from the American Society of Tropical Medicine and Hygiene in 1992; the Legion of Merit from the U.S. Navy in 1993 and 2000; the Col. George W. Hunter III Certificate in 1994; and the Captain Robert Dexter Conrad Award, the U.S. Navy’s most prestigious award for scientific achievement by anyone in any field, regardless of military affiliation, in 1998.

  Mapping the malaria genome was enormously complex, taking $28 million and a lot longer than Hoffman or anyone else anticipated. In fact, it took an international consortium of organizations with scientists from more than a dozen institutions. But the genome work, of which many other experts were at first skeptical, had incredible influence on the field and changed the way malaria research is done. It provided the opportunity to find the genes from the Plasmodium falciparum parasite that would make the best vaccine and drug targets: a chance, as one researcher put it, to “search for the chink in the parasite’s armor.”10

  It also had an important influence on Hoffman. “I realized from all of those different lines of work, all of which people said couldn’t be done, that if you actually organize yourself well, get the right smart people around you, put the story together properly, you can actually accomplish a lot of things everybody said were impossible or impractical,” he told me.

  In the spring of 2002, Hoffman organized a scientific summit through the Keystone Symposia, an independent nonprofit devoted to advancing biomedical and life sciences. One session was titled “Malaria Vaccines: Why Is It Taking So Long?” Hoffman was struck by the predictions of various experts as to when they thought a malaria vaccine might be launched as a commercial product. “Many in the room thought it would be sometime between 2020 and 2025 at the least, even with the genome,” he said.

  Hoffman thought back to the approach that was pioneered by Ruth Nussenzweig at NYU when she showed that she could protect mice against mouse malaria. In the early 1970s, there were two separate groups of researchers who had thought that the same strategy would work on humans and had seemingly proved their point. “It was shown independently that you could protect people by this method, but it appeared to be totally impractical,” Hoffman said. “But this is the lesson I learned: like sequencing the malaria genome, this was a bioengineering problem, not a scientific discovery problem.”

  With this one insight, Hoffman had fundamentally re-imagined and redefined what it would take to create a vaccine to prevent and ultimately end malaria. It was as if he had looked down on the playing field and realized that it would not be good enough to be the first across the goal line; rather, the vaccine development community was playing on the wrong field. Success would require mastering not just the traditional disciplines of biology and immunology, but those of engineering and entrepreneurship as well. It wasn’t that world-class scientific discovery would not be necessary. After all, Hoffman would go on to assemble a team of accomplished scientists from around the world. It’s just that science alone wouldn’t be sufficient.

  When Hoffman described this “bioengineering” challenge to me, I was struck by the similar problem faced in so many dissimilar fields, albeit fields with which I had greater familiarity. In the social sciences it is often presumed that because of the persistence of seemingly intractable problems—hunger, homelessness, teenage pregnancy, unemployment, drug abuse, and so on—we don’t know what the solutions are. In almost every case there are programs that work, programs that address such problems with high rates of effectiveness. But they tend to be local, idiosyncratic, and impractical, for one reason or another, as models that could be used elsewhere. Just as in the case of the Nussenzweig vaccine that Hoffman hopes to manufacture, the challenge is not one of discovering new solutions, but of making the solutions that have already been discovered affordable, replicable, scalable, and sustainable.

  CHAPTER 6

  BATTLEFIELD GENERAL

  Researchers in Melbourne believe their discovery could be a major breakthrough in the fight against the disease.

  The malaria parasite produces a glue-like substance which makes the cells it infects sticky, so they cannot be flushed through the body.

  The researchers have shown removing a protein responsible for the glue can destroy its stickiness, and undermine the parasite’s defence. . . .

  Professor Alan Cowman, a member of the research team at the Walter and Eliza Hall Institute of Medical Research, said targeting the protein with drugs—or possibly a vaccine—could be key to fighting malaria.

  “If we block the stickiness we essentially block the virulence or the capacity of the parasite to cause disease,” he said.

  —Phil Mercer, “‘Breakthrough’ in Malaria Fight,” BBC, July 14, 2008

  ON MY SECOND VISIT TO Stephen Hoffman at his Sanaria office and lab in Rockville, he was waiting for me, and his assistant ushered me into his office immediately. I had the sense that having someone write about him was appealing to Hoffman, that he viewed it as external affirmation that his journey, scoffed at in some circles, was worth observing. In the environment he works in, which is intensely competitive and also marked by routine failure and only occasional breakthroughs, such affirmation is rare. You take it where you find it.

  But he was
also cautious, wary of the idea of an outsider writing about his work, and wary of me, whom he didn’t really know. Much of the lab’s methodology is proprietary, and Hoffman did not want to see it compromised. The methodology is not only critical to the development of a malaria vaccine but could have applications to many other biologic and scientific processes. Sanaria has had to learn how to harvest record levels of parasites from mosquitoes, separate them from other potentially infectious salivary gland material, store and preserve them—all in ways that have created valuable new intellectual property. Hoffman is nothing if not a competitor. And he knows he’s in a marathon race. He’s busy, focused, and disciplined.

  We talked about how his work was different from what he did in the navy for twenty years. As he spoke, he struck me as someone who was ready to take on all challengers. Hoffman has his supporters, some of whom are impressive overachievers in their own right, such as the late Maurice Hilleman, who, at Merck, developed eight of the fourteen vaccines now given to children routinely, and who was one of the first to join Sanaria’s board. But there’s an intensity to Hoffman, the wariness of a man who knows he has skeptics. His chin tilts up a bit, and the air of impatience rarely leaves him.

  Casual in black jeans and cowboy boots, he was fit and trim, even a bit tan. Surrounded by wood-carved art from New Guinea and pictures of his wife, Kim Lee, he tried to explain how he saw his role now compared to his navy years:The way I think about my work is not much different. I never really felt like I had a boss in the navy. I could do what I wanted to do. But this is bioengineering, not scientific discovery. Our job is to develop and manufacture a vaccine. That’s it. That’s what we have to stay exclusively focused on. There are plenty of colleagues who are smarter than I am. What I’m good at is having a vision of what is possible, and putting together all of the pieces to achieve it. Someone has got to be the one to say this is achievable. Most people aren’t able to envision something that hasn’t been in their line of sight before. And so my job is to keep everyone focused on producing the vaccine, that’s it, that is all we are about. And I just keep driving them to do that.

  His ambition was for production at lightning speed. “We’ll need 3,000 doses for toxicology trials,” he told me. “After that it goes to the FDA. I’m not expecting any surprises. They can turn around an answer in thirty days. I’m twelve months away from putting this vaccine in an arm, and eighteen months away from putting it in babies in Africa.”

  As confident as he was, Hoffman was quick to interject a note of caution. “But who knows? A lot of people have tried and failed before. I’ve tried and failed. The first thing I ever did was develop a treatment for severe typhoid fever. That was in 1984. Other than when I was an emergency room doc, there’s nothing I’ve done since that has saved a single human life.”

  That success is the exception rather than the rule seems to be the accepted dynamic in laboratory science. It is the nature of science, the logarithm of scientific advancement and achievement. Most scientists acknowledge it no matter how begrudgingly they accept it. Still, it is one thing to say it and another to live it. Living it means logging late nights and long hours in the lab, measuring and marking and checking and double-checking tests and trials cobbled together from grants that took weeks to write and then months to hear whether they were approved or rejected. Living it means writing highly technical papers that must be peer-reviewed and that, when published, will draw criticism from others with only half the experience.

  In addition to a little bit of luck, it takes a special personality to pull off something like the development of a vaccine: It takes someone with persistence bordering on stubbornness, confidence bordering on arrogance, the long-term patience of a cathedral builder, and the immediate impulses of an emergency-room doc. It takes leadership. And it takes a boxer’s willingness to take a punch and come up off the canvas.

  I was curious how Hoffman’s vaccine was different from the better-known, better-funded GlaxoSmithKline (GSK) vaccine candidate, RTS,S, which was farther along in clinical trials. In 2005, clinical trials in Mozambique for the RTS,S reported efficacy of 29.9 percent, and at the end of the six-month observation period, prevalence of the P. falciparum parasite was 37 percent lower in the RTS,S group compared with the control group. Later trials would show the effectiveness of RTS,S jumping up to 53 percent, an impressive gain, but one that still would leave nearly half the population unprotected.1 Such progress at least ensures continued funding. More than $800 million will be invested in RTS,S before all is said and done, an amount that dwarfs the resources available to Steve Hoffman. If there was a front-running candidate among the various malaria vaccines under development, RTS,S was it.

  RTS,S and Hoffman’s vaccine are both built on what is known about the circumsporozoite protein that the Nussenzweigs identified as a vaccine target. Hoffman was part of the team composed of the Naval Medical Research Institute, Walter Reed Army Institute of Research, and GSK that ran the first clinical trial of such a vaccine. GSK “kept going, and I diverged,” Hoffman explained in an interview with the tropical disease website TropIKA.net. “As Director of the Navy malaria program, my job was to develop a vaccine that could be used for military personnel or travellers, meaning that it had to be at least 80%, preferably over 90%, protective to have the operating characteristics of most other vaccines. . . . I’ve always felt that’s the kind of vaccine we need for everybody—that there shouldn’t be different tiers of vaccines: one for travelers and another for kids in Africa.”2

  At one point in our discussion, Hoffman became animated and went into to another room to get the large laminated malaria life-cycle chart that is the indispensable teaching tool of all malariologists. The illustration is the anatomical outline of a human body from about the shoulder to mid-thigh. It shows a mosquito on the arm and then the rapid flow of parasites through the body, first to the liver, and then bursting out of the liver in a new, more mature cellular form. Now “merozoites,” they head into the red blood cells to do their greatest damage. Hoffman laid the chart down on a table and demonstrated strategy like a four-star general explaining a battlefield map. He leaned over it, pointing out critical areas with broad sweeps of his hand.

  Hoffman used terms like “merozoite invasion” and spoke of the parasites’ skill at “evading defenses.” He explained the possible options and strategic choice he had made, dividing the diagram into three sections, surveying the various battle-grounds: the transmission stage, which represents the other part of the parasites’ life cycle as it gets into and out of the mosquito; the liver stage, or pre-erythrocytic stage, meaning before the merozoites get to the red blood cells; and the final stage where the red blood cells are being affected.

  Hoffman said he is not that interested in campaigns against the merozoites entering the red blood cells. Nor is he interested in the air war of a transmission vaccine—which is also known as an “altruistic vaccine,” because it doesn’t help someone already infected but instead protects the rest of the community by blocking transmission of the parasite from one mosquito to another.

  Hoffman has chosen instead to target the liver as his Omaha Beach. “This is where we’ve got to stop them: in the pre-erythrocytic stage. If they can’t get out of the liver, they die. The T cells will kill them,” he said, speaking of a natural ally the way General Dwight D. Eisenhower during World War II might have spoken of the Brits.

  Years of laboratory reconnaissance have revealed quite clearly how the enemy operates. There are two places where the parasite does its work: One is inside the mosquito, the other is inside human beings. Both represent opportunities to put the enemy out of commission.

  JOURNEY TO THE CENTER OF THE MOSQUITO

  When a mosquito bites an infected person, it ingests the parasite at an early developmental stage. Once inside the mosquito’s midgut the parasites will develop into what are called “sporozoites,” some of which make their way to the mosquito’s salivary gland. The next time the mosquito bites someo
ne, hundreds of sporozoites will be injected into the new victim.

  Here’s how the mosquito pulls it off: A female Anopheles mosquito, hungry for blood, lands on a patch of human skin. Only the female mosquitoes bite, and it’s only because they need the nutrients and protein of a blood meal to be able to make and lay their eggs. Female mosquitoes mate only once, but they store enough sperm to use throughout their reproductive life.

  When it bites, the mosquito probes with a long, needle-thin, tube-like proboscis that actually has four tools inside of it: Two have serrated edges to slice and drill a hole in the donor’s skin, one acts like a hose to inject saliva, and the other is like a straw to draw blood into the mosquito’s body.

  The authors of an article in the Johns Hopkins Public Health magazine described the mosquito’s actions in vivid terms:At the end of the proboscis, knife-like stylets move rapidly like electric carving knives to split the skin. She gently jabs at different angles in the hole until she nicks an arteriole that spouts a subcutaneous pool of blood that she can draw from. Exquisitely evolved, the female vampire will squirt into the cut a small amount of saliva full of anticoagulants to prevent the blood from clotting.

  Within a couple of minutes, her translucent belly bloats and shifts from waxy gray to cherry red. She sucks a few micrograms of blood—more than her own body weight. . . .