The Imaginations of Unreasonable Men

by Bill Shore

  Sanaria was the company he’d formed in 2003, the realization of his dreams for malaria research that he’d first shared with his family at his kitchen table. In August 2007, he moved its headquarters to a much more advanced facility, also in Rockville, where it is part of Maryland’s Biotechnology Corridor.1

  Sanaria has come a long way. When I visited the original site, Suite L on the second floor of 12115 Park Lawn Drive in Keats Plaza, the company’s closest neighbors included a Floor Covering Center and Tri-Graphics Picture Framing. A glass door with small white stick-on letters spelling the company name confirmed that I was in the right place, but from the outside it looked like the kind of space one would rent for a temporary project, maybe a campaign headquarters for county commissioner or an interim sales office. If this was the impression the neighbors took away, I thought, that was just fine. If they’d had the slightest inkling of what they were driving by each day—of what a mild breeze might send toward their doorstep—Steve Hoffman might have had his hands full with a lot more than science and biotechnology.

  Having anticipated test tubes, white lab coats, and state-of-the-art equipment, I felt disappointed at the idea of talking to someone at a desk in this shabby building. The glass door was locked, and I leaned my nose against it to peer in, wondering if anyone was even there. A woman soon appeared, opened the door, and said Dr. Hoffman would be with me shortly.

  She did not have to usher me through a maze of corridors into some inner sanctum to see her boss. Although Hoffman was president of the company, his office was right by the front door (as I found out later, the inner sanctum was reserved for the mosquitoes). There was no place for me to sit, so I just stood there waiting, next to a strange neon blue light that hung down in a wire cage near the corner of the ceiling.

  “Three hundred and nine thousand!” a voice shouted from the other side of a thin plywood wall. “That’s right, 309,000, can you believe it? And that’s just one. Altogether we did 109 million just today.” I could tell that Hoffman was on the phone. There was exuberance in his voice, and confidence, even a trace of mischief. Then I heard other voices and realized he had colleagues in his office. They were sharing in a moment of triumph, celebrating it. But it was his voice that was dominant.

  If we’d been in New York City, I’d have thought he’d made a killing in the stock market that very afternoon. “A hundred and nine million!” he shouted again, even louder, as if it were shares or dollars.

  “You came on a banner day, probably the best day we’ve ever had,” he announced a few moments later. “Right in there,” he said, pointing back to a locked door with universally recognized bio-hazard warning symbols on it, “right there, this afternoon, we dissected the salivary glands of enough mosquitoes to extract 109 million parasites.”

  He wasn’t speaking of just any parasite, but of Plasmodium falciparum, the parasite that causes the deadliest form of malaria. It kills more children—1 million every year—than any other single infectious agent on the planet and is responsible for untold suffering in dozens of countries. It is the U.S. Defense Department’s number one science priority after terrorism, though hundreds of billions of dollars are spent on the latter and only tens of millions on the former. It has been attacked with every strategy known to man, and it has never been beaten.

  With evolution and natural selection on its side, P. falciparum has prevailed over every effort to destroy it. Pitted against the greatest minds, massive resources, and the most evolved technology, beginning with the microscope and through to computer mapping of the human genome, the single-celled parasite has consistently outwitted and out-maneuvered its foes at every turn, somehow managing to keep concealed nature’s deepest and most mysterious secrets. It is a battle that has been truly epic in proportion.

  Listening to Hoffman, I was momentarily distracted by trying to call up a mental image of what it takes to dissect a mosquito’s salivary gland. I pictured small technicians in white coats hunched over large microscopes at flat white tables. My vision was not far off, but it turns out that dissection is the easy part. Breeding the mosquitoes in an environment sterile enough for approval by the Food and Drug Administration, ensuring the vaccine could be stored safely and would remain chemically stable, testing to rule out all possible side effects—these were only a few of the formidable challenges Hoffman faced beyond extracting sufficient quantities of parasite. The process was memorably described by Jason Fagone writing in Esquire: “Hoffman’s vaccine would have to be made inside mosquitoes. It would be like baking a pie in a cow.”2

  My science education was just beginning; I still had a lot to learn. But I knew enough about Hoffman’s vaccine theory to know that this milestone of harvesting 109 million parasites in one day was a critical development. It affirmed that he’d eventually have enough raw material to produce the vaccine at the scale required.

  Although a vaccine would be the ideal way stop the P. falciparum parasite and to prevent malaria, there is not now, and never has been, a licensed malaria vaccine. In fact, there has never been a vaccine for any parasitic disease. The vaccines we are familiar with, for polio, measles, and smallpox, to name a few, are for viruses.

  Sanaria is the only company in the world dedicated entirely to malaria vaccine development. Steve Hoffman is quick to point out its promise. The immunogen—that is, the specific set of proteins that prompts the body to fight back against foreign invaders—that Sanaria was using for its vaccine, he explained,has been shown to protect 13 of 14 (93 percent) of human volunteers against 33 of 35 (94 percent) experimental infections for at least 10 months. No other experimental malaria vaccine has ever been shown to consistently protect more than 40 percent of experimentally infected volunteers for more than three weeks, and no competitor is working on an experimental malaria vaccine with the potential to protect even 50 percent of volunteers against infection for more than a few weeks.

  The ever-resilient, mutating parasite has prevailed over every effort to stamp it out.

  I’d been in Africa, of course, without ever knowingly seeing a malaria-infested mosquito. But here I was in Maryland, in a strip mall just minutes from where I’d lived for twenty years, and I’d stumbled across more than 100 million of them, alive and well—and poised to reproduce virulently.

  HOW MANY TECHNICIANS DOES IT TAKE TO UNSCREW A MOSQUITO?

  For my tour of the lab, Hoffman grabbed his white lab coat off the hook on the back of the door and found a blue one for me to wear that made me look like a hospital orderly. We first stopped by the desk of a young woman named Asha whose job it was to breed parasites. “We create more parasites in one day than the rest of the world does in an entire year,” Hoffman bragged. He is given to statements like these, dramatic calculations that do not fail to impress even though their documentation is unclear.

  The mosquitoes were being bred in large beakers that looked like decanters for fine wine. The larvae and pupae moved jerkily in a cloudy yellow liquid. These specimens would eventually be irradiated for about three minutes at a dose that had been determined to yield the greatest protection, carefully balanced to leave the parasite living within weak enough not to do harm but strong enough to trigger the immune system. After that, they’d be taken into another room. There, lab technicians, peering through large microscopes, were dissecting the salivary glands of mosquitoes and extracting the parasites. After that the attenuated, or weakened, parasites would be frozen by a cryopreservation process. In essence, that means they’d be put into a deep freeze, their temperature lowered below zero so that they could eventually be revived and restored to the same state as before, and then stored. “And so those will go into the vaccine?” I asked. “Those are the vaccine,” Hoffman replied. Once Hoffman completed trials and received FDA approval, he said, the irradiated parasites would constitute the vaccine.

  When Nussenzweig had made her key discovery almost forty years ago, she and her research colleagues had said that the trial had “demonstrated for the first time tha
t a pre-erythrocytic vaccine, administered to humans, can result in their complete resistance to malaria infection.” The battle against malaria, however, was far from over. As Ruth Nussenzweig and her team put it, “since infected irradiated mosquitoes are unavailable for large scale vaccination, the alternative is to develop subunit vaccines.” In other words, vaccines would have to be made from purified pieces of the parasite, rather than whole specimens.3

  Nussenzweig’s approach became known as an “attenuated sporozoite vaccine.” Sporozoite literally means animal seed and is the name for the cell form that infects a host, such as the parasite cells that eventually leave the mosquito’s salivary gland and enters a human’s liver.

  The bottom line, as Hoffman explained, “is that it has always been considered clinically and logistically impractical to immunize large numbers of susceptible persons with the irradiated sporozoite vaccine, because the sporozoites must be delivered alive, either by the bite of the infected mosquito, or potentially by intravenous injection, as is done with mice.” The challenge, then, is first to make an appropriately irradiated parasite, and then to keep it frisky until it can be injected into the target population. All vaccines can be weakened by time and temperature variations. Many a parasite could perish en route from a laboratory in Maryland to a field station in Africa.

  It is in this space between impractical and impossible that Hoffman has decided to bet the ranch.

  Sanaria employed twenty-seven people when I first toured the facility. As we made our way through the office, every section was compartmentalized. There were double-door safeguard systems so that one door wouldn’t open until the other had been closed, to ensure that nothing could escape. A keypad code was required to enter sensitive areas, and in the chamber between the two doors was the ubiquitous blue-light bug zapper. Protective gear was required, but Hoffman gave me the grand tour. I saw the room where the technicians peered into microscopes to dissect the salivary glands, the room where the mosquitoes were irradiated, and the room where the cultures were bred.

  And then as Hoffman speculated about the potential of the vaccine, he got excited again, as he had been on the phone when I first walked in. He told me that one technician working for one hour could dissect a hundred mosquitoes, and that eight technicians working for four hours could produce enough sporozoites to fill the initial clinical trials. Four technicians working for a year could provide enough for the entire military market, and ninety technicians could produce enough for Africa.

  He also explained that, to satisfy the FDA, you have to be able to make four guarantees. He summed them up this way, explaining how Sanaria is meeting each requirement:First is sterility. Mosquitoes are usually bred in swamps or insectaries. But we are breeding in test tubes and ensuring there is no bacteria or fungi.

  Second is purity. We’ve developed a way of producing aseptic sporozoites and purifying sporozoites that has never been done before.

  Third is stability. Can we preserve them in a bottle so that the vaccine will retain its potency when stored? Remember, this is a live, attenuated vaccine, not a dead vaccine.

  And finally, safety, that it will not cause malaria in humans.

  I asked why everyone had been wrong about how many sporozoites could be extracted. “No one actually bothered to find out, including me,” he said. “I was just on the phone yesterday with Ahvie Herskowitz from the Institute for OneWorld Health. He asked me how in the world we kept getting better and better numbers. I said ‘Avi, remember the joke about how to get to Carnegie Hall? Practice, practice, practice,’” and at this he threw back his head and laughed.

  As we were leaving the lab, I asked Hoffman what could stop him from succeeding. He perked up, as if in anticipation of his own answer: “Nothing! Money, of course, is always an issue. And the security of this lab. If some mosquitoes got out and a man across the street came down with malaria that would be it. I’d be dead. Finished. Just meeting the regulatory requirements to build this place was amazing.”

  MAN, NOT MYTH

  No one person stood out as the obvious and logical choice around which to tell this story. In fact, it was quite the opposite. There were many amazing possibilities from which to choose.

  The field of global health is home to Nobel Prize- winning scientists, conquerors of disease, revered humanitarians, and unfathomably wealthy philanthropists. It boasts entrepreneurs like Craig Venter, who won the race to map the human genome, and Victoria Hale, the former Food and Drug Administration official who created the first nonprofit pharmaceutical in order to address neglected diseases. There are leaders of large institutions like the National Institutes of Health, or the Walter Reed Army Hospital, and physicians who have opened small clinics in the most remote jungles and deserts, such as Rick Hodes, who moved to Ethiopia on behalf of the American Jewish Joint Distribution Committee and adopted more than a dozen children in need of complicated surgeries.

  But I wasn’t searching for the perfect choice. Perfection eludes most of us. Imperfection is more representative. It is certainly more universal.

  I sought out Steve Hoffman after becoming intrigued by the way others referred to him, particularly within the tightly knit group of doctors, research scientists, and military and diplomatic officials known as “the malaria community.” It was not what they said so much as what they left unsaid. His name invariably left an invisible but palpable tension in the air, like one of those high-energy transmission towers that can be valuable or dangerous, depending upon your point of view.

  Without knowing anything else about him, I could sense that Hoffman was a complicated man, someone who challenged others’ comfort zones and vigorously protected his own, whose ideas were too radical to simply accept, but grounded in too much experience to casually dismiss.

  Fifty-six years old when we first met, trim and muscular, Hoffman had the guarded and intense demeanor of a competitor watching the game clock run down before his victory is secured. He is skilled at political positioning but lacks the politician’s gift for small talk aimed at surfacing any patch of common ground that can serve as the basis for a relationship.

  He first agreed to see me after receiving a brief e-mail that I’d sent without benefit of introduction from any third party. By coincidence, we’d both graduated from the University of Pennsylvania, and his lab was in my neighborhood. Other than that we had little in common.

  Once we met, though, I began to feel some vague but unarticulated kinship with Hoffman, notwithstanding the fact that our personalities were very different. We had both made the transition from long government careers to long-shot start-up enterprises. We’d both worked in institutions—the navy and the U.S. Senate—that afforded resources, prestige, and access to almost anyone or anything one might need. We’d both traded that away for the pressures and headaches, but most of all the freedom, that comes with a start-up enterprise housed in crowded, makeshift offices and financed paycheck to paycheck.

  I couldn’t walk through his crowded and cluttered lab without thinking of Share Our Strength’s first days in the sub-basement of a Capitol Hill townhouse that had been converted from an electroshock therapist’s facility, complete with sound-muffling egg cartons glued to the walls. I remembered that feeling of having the kernel of a half-baked idea that the rest of the world had yet to hear about or understand, but that, once developed, tested, and refined, might prove to inspire and mobilize others.

  I certainly didn’t put Hoffman’s odyssey at the center of this story because I had the foresight to be sure he would succeed. Indeed, the odds of him reaching his goal are long, if not forbidding. We won’t know the full measure of Hoffman’s success or failure, or that of any of his competitors, until the passage of time has had its way. Many years will be required for conducting and assessing clinical trials. Even if his vaccine makes it through those hurdles and a successful vaccine is put into wide use, the malaria parasite could evolve to escape defeat, as it always has in the past. There are an infinite number of va
riables, ranging from climate change to African infrastructure, that may have more to do with whether the vaccine works on the ground than anything Hoffman does or doesn’t do in the lab. And there are other possible breakthroughs on the horizon that could blow Hoffman’s ideas out of the water. Scientific discovery, by its very nature, stands still for no man.

  But the trajectory of Hoffman’s life and career so clearly parallels and illuminates our society’s changing approach to solving social problems. He began as a doctor doing what doctors do, helping one person at a time. But as he became interested in tropical diseases like dengue fever and malaria, he came to see that the scale of the problem and the enormous number of people affected was far greater than what any one doctor could handle. It was greater even than what all the doctors in the field of tropical medicine could handle. And the problems were not just medical, they were economic and political.

  When he realized it would take the resources of government to solve the problems he cared about on the massive scale on which they existed, he joined the U.S. Navy, which had the best facilities at the time, and eventually led its malaria vaccine development efforts. The goal was not just delivering good medical care, but scaling up that care so that others would have access to it. Lacking an economic market for doing so, Hoffman found a political market in the form of government. For twenty-one years, the U.S. Navy and Army offered the tools necessary to advance vaccine development.

  But after a certain point, he also came to see the limitations of what could be done via government. He then became the classic entrepreneur, resigning from government, setting out into the private sector, and starting a company—a biotech company. He chose to operate at a new intersection of philanthropy and entrepreneurship that would permit him to take risks and try out innovative ideas in order to solve problems that there were no economic or political markets for solving.