The Imaginations of Unreasonable Men

by Bill Shore

  THE IMAGINATIONS OF UNREASONABLE MEN

  The three philosophical underpinnings of breakthrough thinking described above—(1) that good is not good enough, (2) that most failures are failures of imagination, and (3) that irrational self-confidence is essential—are not by themselves a solution for our toughest problems. They are not even a shortcut to such solutions. But they are the necessary architecture for solving them, the underpinnings without which most efforts will falter.

  Just look around. We are surrounded by the monuments of men and women who failed to recognize the stop signs along their journey to solving a problem or creating something new.

  As Dan Pallotta, founder of the ambitious and wildly successful AIDSRides, bicycle rides to raise funds for AIDS service organizations, once said to me: “Don’t you suppose someone must have argued to Henry Ford: ‘But that’s crazy—you’d have to build these gas station places all over the country and pave these incredibly long roads.’” Great imaginations are almost always unreasonable, but they almost always triumph in the end.

  Most of us won’t cure malaria or invent the next automobile. So why are these elements of breakthrough thinking important in our own lives? Can they apply to each of us? They do if we believe that the organizations, communities, and world of which we are a part can do better. They are important if we’re frustrated with the slow and incremental pace of social change, or if we wish to play some small role in lightening the suffering and struggles of those less fortunate with whom we share this planet. They are the qualities that allow some people, gifted with great vision, to insist that, rather than taking the reasonable approach of adapting to the world, the world, in George Bernard Shaw’s words, must adapt itself to the unreasonable man.

  CHAPTER 2

  WHATEVER IT TAKES

  Researchers at Edinburgh University’s Institute of Cell and Molecular Biology have isolated part of a protein which allows [malaria] to become resistant to new treatments. . . .

  Professor Malcolm Walkinshaw, of Edinburgh University, said: “We can now use this protein structure to design a new generation of drugs which makes it possible to overcome resistant strains of malaria.

  “People have studied this protein for a long time, but until now, no one has been able to determine its detailed structure. This is a real breakthrough.”

  —BBC News, “Malaria Treatment Breakthrough,”

  April 22, 2003

  STEVE HOFFMAN IS A DOCTOR who wants to develop a vaccine to prevent malaria. If it works it will save the lives of millions of children. If it doesn’t, he will find company in the ranks of countless others who have gone before him, tried, and failed. And millions will continue to perish in an agonizing death.

  While there are vaccines for bacteria and viruses, there has never been a vaccine for malaria, or for any parasitic disease.

  The reasons are both scientific and political. The parasite is complex, elusive, and even brilliant, in an evolutionary sense. And most of those whom it infects are so voiceless, vulnerable, and marginalized that there are no markets—economic or political—for serving them or solving the problems they face. They are victims not only of malaria but also of chronic political laryngitis. And their condition persists not because of the paucity of solutions, but because they have no political voice. Society has not been fully persuaded to pay for solutions that already exist. Nor are there many who are willing to share in the sacrifice of time and money that would be required to sustain those solutions and take them to scale.

  Instead their fate depends not on traditional approaches but on an emerging new cocktail of entrepreneurship, philanthropy, and science—stirred by imagination—a cocktail being developed by Steve Hoffman and a handful of colleagues and competitors around the globe.

  AN UNSTOPPABLE FORCE

  Steve Hoffman has practiced medicine for more than twenty-five years, but his ambition has required him to wear many hats: that of naval officer, business entrepreneur, research scientist, author, evangelist, employer, fundraiser, humanitarian, and biotech engineer. He has the necessary personality traits to go with them: brilliant, innovative, confident, arrogant, impatient, stubborn, charming, abrasive, driven, determined, and competitive.

  One particular quality dominates all of the others, giving Hoffman’s quest its unstoppable force: He is prepared to do whatever it takes to save millions of children’s lives.

  When, in 1980, it meant leaving a comfortable medical practice in San Diego and joining the U.S. Navy in exchange for access to the best research tools, labs, and clinics, a young Dr. Hoffman cut his hair, shaved his beard, and enlisted, shipping out to Indonesia, which at the time hosted our government’s most advanced infectious disease research lab in the tropics.

  When, in 1987, it meant testing the safety and effectiveness of a potential vaccine he’d helped develop, Hoffman rolled up his sleeves—or, literally, a sleeve—and let a swarm of mosquitoes drink blood from his arm until they transmitted in their saliva enough deadly parasites to make their way to his liver. That vaccine failed and he proceeded to get violently ill with the chills, shakes, and fever of malaria.

  When it meant starting a private biotech company to pursue a vaccine-development approach that every other expert dismissed as impossible, he retired as a navy captain and, in 2003, started the business with his wife and son at their kitchen table, raising the capital, hiring the technicians, and quietly constructing one of the most unusual laboratories in the world to extract microscopic parasites from the dissected salivary glands of live malaria-infected mosquitoes.

  When it meant establishing his authority as an expert with whom others would collaborate and invest, he experimented, researched, and wrote more than 350 papers over the years, becoming the most cited author in the world for scientific articles on malaria.

  And when it meant convincing a skeptical scientific community that there was a viable alternative to the better-known vaccine being tested by GlaxoSmithKline, the fourth-largest pharmaceutical company in the world, he packed up his PowerPoint slides and flew to international conferences in Dakar, London, Nairobi, Amsterdam, and countless others cities to stand alone and make the case for his unusual approach.1

  Whatever it takes.

  But whenever one mentioned Steve Hoffman’s name to his colleagues, those who were accepted as members of the small, dedicated fraternity of tropical disease specialists who had also dedicated their lives and careers to battling malaria, you’d get the kind of silence, stare, or stutter that prompted you to change topics. Eyebrows arched. Heads shook. The skepticism was palpable. Nevertheless, it was leavened with respect and sometimes envy. When someone is willing to do whatever it takes, you never quite discount him. I, for one, was incredibly intrigued.

  I first heard Steve Hoffman’s name in 2005 when it was mentioned to me by Dr. Diane Griffin, who chaired the Department of Molecular Microbiology and Immunology at Johns Hopkins University’s Bloomberg School of Public Health, the largest school of public health in the world, named for its largest donor, New York businessman and mayor Michael Bloomberg. The Oklahoma-born Griffin had been lured there from Stanford University, along with her husband, in 1970. She had become an assistant professor in 1973, an associate professor in 1986, and, eight years later, chair of the department. When she spoke of Hoffman, she almost giggled. That was when I knew I had to find out what he was up to.

  “AND THEN THERE’S THIS WILD THING STEVE HOFFMAN IS DOING”

  Griffin’s own specialty has been the measles virus. In May 2001, though, the Bloomberg School received a $100 million gift to be used in the battle against malaria. Dr. Griffin, a well-respected veteran researcher on how viruses create infectious disease, with 275 published papers of her own, was tapped to establish a Malaria Research Institute and to map a strategy and attract the talent that would make it distinctive.

  Her work on measles has been impressive. In America, vaccinations keep us safe from measles, but the disease still takes the lives of tho
usands of children in developing countries. It was Griffin who discovered that the measles virus could suppress the release of the protein Interleuken 12, weakening the body’s natural immunities. This effect makes measles especially dangerous in developing countries because it leaves children vulnerable to other infectious agents, such as pneumonia and malaria. Her research has led to work on several promising vaccines.

  “I’ve always been interested in problems that affect those without a voice,” she explained. “Malaria is very different from AIDS, which affects adults who can organize themselves and lobby.” She is particularly focused on how the fight against malaria has been fought to a stalemate:The vaccine efforts around malaria haven’t changed for thirty years. They need new input. Even the diagnostic blood smear is the same. And more children are dying from malaria now than died ten years ago. . . .

  We believe that there is no magic bullet, and therefore when we got the grant we decided to recruit broadly and tackle the issue at all points. We’ve developed a somewhat unique emphasis on the mosquito, rather than the parasite. Historically, success has always been a result of controlling the means of transmission, which we call the vector. At our first international conference on malaria, which was dominated by vaccine people, many had been so focused on the parasite that they had not heard talk of mosquitoes before.2

  Dr. Griffin generously offered to set up a meeting for me with “the mosquito people,” a team that was working on a vaccine to prevent transmission of malaria from mosquito to mosquito. “The only progress that’s ever been made with malaria has been in controlling its vector,” she said. If mosquitoes can’t transmit malaria to each other, then transmission to humans begins to decline also.

  Finally, almost in passing, she mused, “And then there’s this wild thing Steve Hoffman is doing. He used to run the navy’s program and apparently has all of these people out in a lab somewhere, all bent over their desks dissecting live mosquitoes.” I could see from the girlish grin she flashed and the way her eyes lit up that she found an element of eccentricity in what Hoffman was doing. And while she said no more, I also sensed she wouldn’t have mentioned it if she didn’t know and respect Hoffman.

  In a field that has suffered a stalemate for many years, eccentricity might be just what is needed. Hoffman sounded like renegade of sorts. I guessed that he’d been driven by urgency and frustration to journey from the establishment figure he once was—with its uniforms, salutes, and rulebooks—to counterculture rebel.

  I made a mental note of Hoffman’s name. When I got home I discovered that his medical and scientific credentials were impeccable. Educated at the University of Pennsylvania and Cornell and with a diploma from the prestigious London School of Hygiene and Tropical Medicine, Hoffman became a captain in the navy, rising to direct the malaria program at the Naval Medical Research Center, and coordinated the Department of Defense’s malaria vaccine development efforts. He had 340 scientific publications to his credit, had received the navy’s most prestigious award for scientific achievement, and had served as president of the American Society of Tropical Medicine and Hygiene. He’d been recruited by Craig Venter, the maverick biologist who raced the U.S. government to sequence the human genome, to become a senior vice president at Celera Genomics.

  Having risen to the very top of his field, he then walked away from it all—from the opportunities for financial gain at an industry leader like Celera, and from the resources and security of a large and powerful institution like the U.S. Navy. Instead he was now laboring away in near obscurity—and as the occasional target of ridicule and scorn—in a small lab he had cobbled together from scratch. I couldn’t think of anyone I’d rather meet.

  CHAPTER 3

  STRANGE BEDFELLOWS

  A team of Monash University researchers . . . has made a major breakthrough in the international fight against malaria. . . .

  The team . . . has been able to deactivate the final stage of the malaria parasite’s digestive machinery, effectively starving the parasite of nutrients and disabling its survival mechanism.

  —Science Daily, “Breakthrough to Treat Malaria,”

  February 8, 2009

  IN 1943, GENERAL DOUGLAS MACARTHUR, the U.S. commander in the Pacific, said: “This will be a long war if for every division I have facing the enemy I must count on a second division in hospital with malaria and a third division convalescing from this debilitating disease.”1 During the Solomon Islands campaign, malaria caused more casualties than Japanese bullets, and after the initial landings on Guadalcanal, the number of patients hospitalized with malaria exceeded all other diseases. Some units suffered 100 percent infection rates, with personnel sometimes being hospitalized more than once. Though we were ultimately victorious over the relentless Japanese military, another even more daunting foe—the malaria parasite—remained undefeated.

  In fact, malaria was a prime concern of military commanders the world over long before World War II. Alexander the Great is believed to have been killed by malaria at the height of his powers. The disease wiped out the army of France’s Henry II in the 1500s. One of the first expenditures of the Continental Congress during the American Revolutionary War was $300 to buy quinine to protect General Washington’s troops. Ten thousand soldiers died from the disease during the U.S. Civil War, and there were at least 600,000 cases, primarily in the South Pacific, during World War II. In some areas of the South Pacific, malaria rates were four cases per person per year. The end of our campaign in the Pacific marked the beginning of escalating combat against this dangerous killer.2

  Malaria causes flu-like symptoms: chills, headaches, nausea, and vomiting. It can escalate, at any age, into anemia and punishing fevers, convulsions, and coma, but is fatal mostly to children under five. Kidney failure, a ruptured spleen, pulmonary edema (fluid buildup in the lungs), cardiovascular shock, and collapse are all potential outcomes.

  Its most dangerous form is cerebral malaria, in which the blood vessels carrying blood to the brain become clogged. Red blood cells that have been invaded by parasites develop knobs on their surfaces, which enables them to cling and stick to the capillaries and small blood vessels. The parasite means no harm—it’s merely trying to avoid being sucked into the filter of the spleen, whose job it is to weed out and destroy damaged red blood cells. Left untreated, cerebral malaria destroys blood vessels in the brain and is fatal in twenty-four to seventy-two hours.

  The surest way to know whether you have malaria is to have a diagnostic test where a drop of your blood is examined under a microscope for the presence of malaria parasites. Even this simple and reliable procedure is problematic in Africa, where cultural issues create a reluctance to give blood. (Scientists at the Johns Hopkins Malaria Research Institute are experimenting with a urine dipstick test that they hope will have greater utility.)

  For hundreds of years, quinine was used to treat the effects of malaria. Quinine allowed the body to build up a substance called heme that was toxic to the malaria parasite and could clear it from one’s system. It was not used to eradicate the disease but to mitigate its effects in anyone who contracted it. Quinine was derived from the bark of the cinchona tree, originally confined to the Andes Mountains of South America, but smuggled to other countries because of its curative powers. The tree is now found in Bolivia, Java, and India, among other places. Like most natural remedies, the supply is constrained, which increases the price. There are forty species of cinchona, which was named for a Peruvian countess. One accesses its curative powers by beating the tree trunks and then removing the peeling bark. One or two grams of ground or chopped bark boiled in water yield the quinine, which is an alkaloid chemical. Its active ingredients were farmed and manufactured synthetically.

  When the supply from South Pacific countries was cut off by a Japanese military blockade in 1941, the U.S. military began to focus on drug research and development. In 1934, research by German scientists to discover a substitute for quinine led to the synthesis of sontochin. Duri
ng World War II, French soldiers happened upon a stash of German-manufactured sontochin in Tunis and handed it over to the Americans. American researchers made slight adjustments to the captured drug to enhance its efficacy. The new formulation was called chloroquine. Because it could be synthesized in the lab and therefore cheaply mass-produced, chloroquine revolutionized treatment of malaria, pushing quinine to the sidelines.

  By the 1960s, resistance to chloroquine had developed and spread. Mefloquine was then created. Mefloquine kills parasites once they enter red blood cells and stops them from multiplying further. But no one is exactly sure how it does so. The prevailing theory is that, like chloroquine, it works by blocking the action of a chemical that the parasite produces to protect itself. The parasite digests hemoglobin and keeps the globin, but heme is toxic to it, so it produces a chemical that converts the heme into a harmless compound. It’s like eating blue crabs and keeping the meat but throwing away the awful-tasting gills.

  Lariam—the brand name under which mefloquine is sold—is strong stuff. Its influence is felt beyond the parasite it is designed to kill. Its side effects range from severe depression and paranoia to vivid dreams. So, in addition to its expense, its toxicity makes it impractical as a long-term solution. It is also a drug that works only to mitigate the disease. It is only a temporary substitute for a vaccine.

  In 1941 our armed services began collaborating with universities and pharmaceutical companies and produced a new arsenal of effective synthetic alternatives. But during the Vietnam War, resistance to the drugs emerged. In 1963 the U.S. Army began a new program that produced two dozen more antimalarial drugs within eleven years. Still, in Vietnam the disease reduced some combat units by half, and it became ever more apparent that vaccine development was a worthwhile investment.