The Imaginations of Unreasonable Men (6 page)

Hoffman’s path could not have been more different from Ballou’s. He didn’t join a company but started one, creating Sanaria at his kitchen table. While Ballou was ensconced on GlaxoSmithKline’s vast Belgian campus, tapping into the expertise of thousands of scientists, Hoffman was cobbling together a start-up with his wife Kim Lee and his three sons. Dissatisfied with the efficacy of RTS,S—“That’s not a vaccine that could ever be considered for use in the developed world”—Hoffman returned to the Nussenzweig discovery regarding the potential of the weakened parasite to serve as a vaccine, obsessed with the fact that it actually worked, even if no one could figure out how it could be made.

At that kitchen table Hoffman set out on a path considered so impractical, so unreasonable, that even the Nussenzweigs held no hope that his goals could be achieved. Build a lab that could breed mosquitoes, and dissect their salivary glands in search of sufficient quantities of parasites to inoculate hundreds of millions of children on the other side of the planet? The question was not what could go wrong but what wouldn’t. Growing sufficient parasites? Harvesting them sterile and pure from the salivary gland, of all places? Keeping this “vaccine” stable and effective as it was transported thousands of miles to Africa or Asia? And delivering it how—by shot? By pill? By the bite of mosquitoes?

But Hoffman didn’t have a boss or board to stop him, or a bureaucracy to slow him down. For the first time in his career he would report to no one but himself, be accountable to no vision or ambition other than his own.

Unlike the time he spent working with Venter at Celera, though, this time there was no billion-dollar bankroll. The venture required classic bootstrapping, one small step at a time, each glimmer of progress parlayed into a hopeful headline that would yield more funding and more glimmers.

Though in the beginning Hoffman and Ballou were more collaborators than competitors, as the stakes grew higher their rivalry grew sharper and ultimately fierce. Tens of millions of dollars had already been invested in and by each scientist. Hundreds of millions of dollars more were on the table. Neither was growing younger. Each had
something to prove. Though they were no longer in the military, it was soon hand-to-hand combat all over again.

Each sought to turn his adversary’s strengths against him and to turn his own weaknesses into assets. In contrast to GlaxoSmithKline’s enormous bureaucracy, Hoffman could be agile, take risks, and work outside of the glare of the spotlight. GSK, on the other hand, could use its size, money, and media machine to maintain momentum even in the face of less-than-compelling results.

For all of GSK’s enormous advantages in resources, Hoffman maintained one leading edge. Large corporate institutions like GSK are not usually the best places to foster imagination or creativity. As William Deresiewicz, a former Yale professor and a widely published literary critic, cautioned the incoming plebes in a lecture at West Point in October 2009:

The implication is more than a little unfair to Rip Ballou, a good and dedicated man working with thousands of talented and committed people, and actually saving lives. But though unfair, it is not invalid. Hoffman has a way of looking at the same things everyone else is looking at and seeing something different. I sometimes have wondered how he suffered the hierarchy of the military for so many years, or how they suffered him. But it’s no accident that a man of such imagination, a man for whom good is not good enough, is achieving his greatest success while not part of some bureaucracy, whether military, corporate, or governmental.

—
Themedguru.com
, “Attacking Malaria by Nipping
It in the Bud—Study,” June 4, 2008

 

 

 

I
N FEBRUARY 2006, WHEN I first made plans to visit Steve Hoffman at Sanaria, I expected to find him in a shiny high-tech complex or an industrial park, perhaps on a sprawling campus. Instead, Mapquest turned up a small strip mall in Rockville, just a few minutes from where I used to live in Silver Spring, Maryland. It was in a neighborhood
of nondescript self-storage centers, U-Haul lots, and home-furnishing suppliers.

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.
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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.”
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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,

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.

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 that 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.
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