The Imaginations of Unreasonable Men (19 page)

To demonstrate the fragility of the chain of discovery, in which happenstance is everything, Ruth Nussenzweig told me how she had come to make her contribution. She had met Victor, her husband and collaborator, at the entrance exams for medical school in Brazil about sixty years ago. She was originally from Austria:

When I asked her if anyone had tried this before, she said:

Though it was other researchers who documented that the same concept would work with humans, it has always been Ruth Nussenzweig who was credited with proving that
the irradiated parasites could act as an immunity-triggering vaccine. She and Steve Hoffman would see each other at conferences. In 2008 her life’s work was recognized with the award of the Albert B. Sabin Gold Medal for her pioneering efforts. Whichever of the many competing malaria vaccines eventually succeeds, it will owe its genesis to her.

So it was symbolic and right that Dr. Nussenzweig should have guided the audience through a PowerPoint presentation of the vaccine’s history, offering an occasional touch of nostalgia when asking, “Steve, you remember this?” “They say you cannot do better than nature. Well, one can, and Steve is succeeding,” she said, almost echoing Jay Keasling’s words. When she was finished she was given the day’s only standing ovation.

Steve Hoffman wore a dark suit and blue striped tie, and the relaxed glow of someone whose day had come at last. He served as host, master of ceremonies, audiovisual technician, speaker, and object of admiration and acclaim. He introduced Anthony Fauci as “the most respected physician scientist in the world,” and Fauci, winner of the Presidential Medal of Freedom for his work on HIV/AIDS, returned the compliment, acknowledging it as “an historic day” and explaining that he’d first met Steve in the late 1980s and had found him to be “a doer of the highest magnitude.” He recalled sitting next to him at a dinner when they agreed it would take a Manhattan Project approach to address malaria. He said Hoffman had “the insight, talent, energy and drive to take a vision and follow it.”

For the past few years he and Hoffman had met every six months. Praising the vaccine for being built on a well-founded scientific concept, Fauci said that “the big hurdle to overcome is the technical challenges, whether it could be produced in sufficient quantities and meet regulatory hurdles.”

When Regina Rabinovich of the Gates Foundation spoke after Fauci, she explained that the foundation had searched for the infectious diseases whose toll represented the greatest inequality and the greatest disparity. She shared the foundation’s introspection on the issues of “‘Are we being ambitious enough?’ ‘What do we want to achieve 20 to 30 years from now?’” and said, “The answer to those questions probably means having to develop different tools.”

Jeff Sachs, director of the Earth Institute at Columbia University and advocate for the Millennium Development goals to fight poverty in the developing world, was complimentary of Hoffman but argued that “bed nets are the tool we have now” and said he couldn’t believe “how hard it is to get rich people to give a small amount of money for bed nets.” Kent Campbell, the program director for the PATH Malaria Control and Evaluation Partnership in Africa (MACEPA), made the point that it was possible to actually change the epidemiology of malaria by going rapidly instead of incrementally.

Hoffman used his time at the podium to share the credit with his team, and to acknowledge the role of Ruth Nussenzweig and an early coauthor named Tom Luke, but
principally to emphasize that what everyone had thought was impossible had instead turned out to be possible because of bioengineering and applied biology. Radiating infected mosquitoes weakens the parasite that resides in the mosquito’s salivary glands enough that the attenuated parasite will trigger natural immunity without actually making one sick. The challenge is in then dissecting the salivary glands and harvesting enough of the sporozoites to equal 1,000 bites of a mosquito, which is nature’s threshold for conferring immunity over time.

He gave the vaccine battle plan’s time line, explaining that three days after it is in the liver the parasite is 3 to 5 microns in size, a micron being one-millionth of a meter. But if they have been irradiated, they stop growing, which advances the goal of ensuring that no parasite gets out of the liver and into the bloodstream.

Aseptic mosquitoes go from eggs to larvae to pupae in nine days in a flask. By day fourteen they are ready to feed on infected blood. After feeding, they sit for sixteen more days before being irradiated, dissected, and put in a vile.

The real challenge was to make sure the vaccine was free of pathogens, free of bacteria and fungi, and free of salivary-gland material (from which people can have allergic reactions). For this, Steve and everyone else acknowledge the indispensable role of Steve’s wife, Kim Lee. She never spoke or presented from the podium, perhaps because her contribution represents such proprietary intellectual capital that very little could be said about it.

Hoffman was transparent about the difficulties that lay ahead for introducing the vaccine into human beings. “We still don’t know how to give it. Before it was given by the bite of an infected mosquito. We can’t do that. We don’t know the number of doses or the interval between them, and so we have to do a dose escalation study. I don’t know if this will be administered subcutaneously, or muscular, or what. There’s no way to know.” What is the best route? The best volume? The best site on the body? Steve is the first to admit that he doesn’t know.

By the end of the day at Sanaria’s ribbon-cutting ceremony, the government officials had moved on to search for new limelights in which to bask and the audience had thinned somewhat, leaving mostly longtime and hard-core malaria advocates spread out among the folding chairs that stretched to the back of the room.

Superlatives continued to echo through the air. Almost everything that could be said about the path to Steve Hoffman’s vaccine development strategy and its wisdom had already been said. But the closing speaker, John McNeil, from PATH, following at least a dozen other distinguished dignitaries, gave the day its exclamation point. He quoted a memorable line from Maurice Hilleman, the creator of vaccines for mumps, measles, rubella, chickenpox, and hepatitis B,
and discoverer of more than three dozen vaccines in all, who is widely believed to be the most successful vaccinologist in history.

McNeil reminisced for the audience about the time Hilleman told him, “If you want to get rid of malaria, kill it in the liver. That’s where the war will be won!” Since Hilleman died in 2005, he has become an even greater icon in global health circles. Quoting his recommendation for a vaccine that attacks the
Plasmodium falciparum
parasite in the liver was like quoting General Dwight D. Eisenhower on how to repel an invasion of Europe.

I thought back to the time many months before when Hoffman had leaned over the large illustration of the parasite’s life cycle. Vaccinologists often fall back on military terminology. They use the language of invasion and resistance, attack and defend, kill and protect. One reason may be that many of the men and women working in tropical medicine had little choice but to enlist in the military, which used to have the best, if not the only, research labs. Their discipline, precision, and language was shaped in that crucible. They respect the parasite as an elusive and deadly adversary, one that has historically been able to withstand everything they threw at it and come back stronger.

But the effort to eradicate malaria resembles war in many ways that go beyond the language of metaphor. First and foremost, it is truly a battle to the death. The victors will survive and the losers will perish. The effort continues until, like war, the opponent is vanquished. But it is a war
being fought not against the backdrop of a visible political agenda, whether extremist, ethnic, or imperialist, but instead in the nearly invisible vortex of evolution’s long and seemingly infinite forces. If the Cold War was, in the words of President John F. Kennedy, “a long twilight struggle,” the war against malaria is one of the longest of all evolutionary battles. It has entailed deception, reconnaissance, aggression, stealth, and lethal weapons.

Allied medical experts in every corner of the globe find themselves both competing and collaborating to identify the malaria parasite’s point of greatest vulnerability. Thus, in Zambia, at the Malaria Institute of Macha, 80 miles from Lusaka, the staff of the Johns Hopkins School of Public Health study why some kids get severe malaria and some do not.

In Uganda, Sweden’s Karolinski Institute and Makerere University study how the malaria parasite conceals itself in the placenta of pregnant women, causing women with their first pregnancy to lose the immunity usually found in African adults.

Tony Holder at the National Institute for Medical Research in London targets the blood stage to see what must be done to lock out merozoites from red blood cells. David Kaslow at NIH is working on a vaccine that mosquitoes would suck up in human blood. It would stop the parasite from reproducing within the mosquito and put an end to mosquitoes being able to transmit the parasite.

The Centre for Novel Agricultural Products at the University of York is using $13.6 million from the Gates Foundation
to fast-track a breeding program for the sweet wormwood plant (
Artemisinin annua
) to create nongenetically modified varieties that will increase yields.

In 2010, the United Nations Children’s Fund, UNICEF, will distribute 25 million insecticide-treated bed nets to protect children from being bitten at night by malaria-infected mosquitoes.

In research funded by the Wellcome Trust and the National Institutes of Health, a study led by Dr. Nick Beare of the St. Paul’s Eye Unit in Liverpool has shown that changes to the retina were the only clinical sign or laboratory test that could distinguish between patients who actually died from cerebral malaria and those with another cause of death. These changes are visible with just an ophthalmoscope, making it possible to track the disease in Africa, where there’s a shortage of expensive medical equipment.
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Malaria cases soared in the KwaZulu Natal province of South Africa after it stopped using DDT in 1996, and the reintroduction of DDT in 2000 brought the disease back under control. That is enough for other countries, such as Uganda and Kenya, to examine whether DDT could also work for them. The Ugandan minister of health, Jim Muhwezi, recently defended the plan to use DDT for indoor spraying in his country, emphasizing the need for a proactive rather than reactive strategy against malaria.

Researchers at the Johns Hopkins Malaria Research Institute, whose malaria control strategy is premised on replacing malaria-carrying mosquitoes with malaria-resistant mosquitoes,
determined that genetically modified mosquitoes, known as “transgenic,” fared better than their natural counterparts when fed malaria-infected blood. Such mosquitoes block transmission of the deadly parasite. The success of their theory depends on transgenic mosquitoes producing more offspring and having lower mortality than natural wild mosquitoes.

These are only a handful of the efforts underway at universities, schools of medicine and public health, field clinics, military labs, pharmaceuticals, nonprofits, and global health organizations. As in war, there are soldiers and there are generals, and among the generals a few of the most daring become known throughout their field and then beyond it.

The ongoing size of the struggle was confirmed by the final speaker at Hoffman’s ribbon-cutting event. Dr. Adel Mahmoud, president of Merck Vaccines from 1999 to 2005, who now teaches at Princeton University’s Woodrow Wilson School of Public and International Affairs, offered a sober note of warning: “A vaccine in the next year or two? Come on, folks, let’s be real. It’s going to take a lot longer than that. Eradication? It’s a nice goal, but we have eradicated only one disease in all of history, and that of course is smallpox. In not one vaccine today do we understand the mechanism of protection. Not one.”

The bet laid down in Rockville is that, long odds notwithstanding, man’s creative genius—at least one man’s—will win out in the end. In a way, it is as if Steve Hoffman has borrowed a lesson from one of Barcelona’s most celebrated
creative geniuses—not his friend and competitor Pedro Alonso, but the late Antonio Gaudi. The fabled, iconic architect built his models from nature, capturing the geometry of structure and adopting essential principles from the lines, shapes, fibers, and textures he observed. Believing that natural structures had millions of years of perfect functioning to their credit, Gaudi often mimicked them in his work. From seashells to beehives, from mushrooms to ears of corn, the ingenuity of nature, for Gaudi, offered clues to effective function. He once said that nature was “the Great Book, always open, that we should force ourselves to read.”
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