The Imaginations of Unreasonable Men

by Bill Shore

  Still, the conference was a success in some significant ways, and Sanaria was still making progress: “I think it is fair to say that people at the ASTMH conference were blown away by the results we showed,” Hoffman said. Sanaria’s was “the only vaccine with a high rate of effectiveness over time. None of the others show that. None of the others come close. Melinda Moree [the director of MVI] introduced me and it was a very nice introduction.”

  Hoffman emphasized that he only gave part of the presentation and the rest was by his team, whose growing size and diversity further impressed the attendees as an indication of Sanaria’s financial health.

  I asked Hoffman who his skeptics were at the Atlanta conference and he described them as “the GSK/Walter Reed axis.” GlaxoSmithKline and the Walter Reed Army Institute of Research have had a long partnership developing a vaccine. Hoffman is publicly polite about their effort, but privately skeptical, especially of how they report their clinical trial results.

  He explained that his critics were skeptical that Sanaria would be able to freeze the vaccine in liquid nitrogen, a step that would be essential to storing and transporting it. Just talking about it brought out Hoffman’s competitive streak. “First they said we couldn’t get enough sporozoites, then they said we couldn’t do it and keep it sterile,” he said. “Then they said we couldn’t keep it stable. And we proved them wrong on all of those. So now they’re saying there will be problems with the liquid nitrogen.”

  We talked about what comes next now that the money had been secured. The immediate focus was on building the new manufacturing facility in Rockville. It would have to meet the FDA’s GMP standards for Good Manufacturing Practices. The other major goal was to finish the toxicology studies and then begin clinical trials.

  In one sense, Hoffman had cleared the highest hurdle of funding—getting that first big break and the recognition that came with it. But in another he had graduated to a sweepstakes where the odds were even more daunting. The Food and Drug Administration’s drug-approval process is an obstacle course and endurance trial so Byzantine, costly, and time-consuming that, while many enter, few come out the other side. Gaining drug approval makes running for president look like an inexpensive walk in the park.

  “We should submit our IND by the first quarter of 2008,” Hoffman said, referring to the mandated Investigational New Drug Application Process. The IND shows results of previous experiments; how, where, and by whom the new studies will be conducted; the chemical structure of the compound; how it is thought to work in the body; any toxic effects found in the animal studies; and how the compound is manufactured. It becomes effective if the FDA does not disapprove within thirty days.

  After phases one, two, and three of clinical trials, a drug being developed finally files a Biological License Application, which provides data attesting to the safety and effectiveness of the vaccine. It typically runs more than 100,000 pages. Statistics about drug approval in the United States give an idea of the long odds Hoffman faces:• Only 5 out of every 5,000 compounds that manage to enter preclinical trials make it to human testing.

  • The average length of time it takes to get a drug from lab to pharmacy shelf is twelve years, and the average cost to get it there is more than $1 billion.7

  Of the many labels I’d used to describe Hoffman—physician, naval officer, research scientist, fundraiser, evangelist, biotech engineer—I now added one more: gambler.

  Steve Hoffman not only has to bet on the long odds of getting his vaccine from lab bench to pharmacy, but then must place a second bet that he’ll get there ahead of all the competitors working on different vaccines that may prove more effective or affordable.

  The nearly $30 million from Gates and via the Malaria Vaccine Initiative allows Hoffman to cover his bet, but nothing more.

  His work, like that of so many of his rivals, still depends on what idealism, imagination, and persistence can achieve in that narrow but vitally important space between the impractical and the impossible. It is a space I have come to think of as the imagination gap.

  The imagination gap is a place where hope lies waiting to be discovered, and cannot be extinguished once it has. Most failures in life are not failures of resources, or organization, or strategy or discipline. They are failures of imagination. It can be a very lonely space, where one faces skepticism and even ridicule, often from one’s own colleagues, a place that one can escape from intact only with sufficient reserves of confidence, stubbornness, and steely resolve.

  CHAPTER 7

  THE E WORD, ONCE AGAIN AND AT LAST

  British scientists have pioneered a vaccine against malaria that they believe could save millions of lives. . . .

  Adrian Hill, a professor from Oxford University’s department of medicine, who is heading the project, last night confirmed the breakthrough. . . .

  “What is different about our approach is we are trying to stimulate a different arm of the immune system as the parasite lives inside the cells most of the time,” Prof Hill said. . . .

  The new approach promotes the production of vital immune cells known as “T cells” in the body, which then destroy malaria infected cells.

  —John Schutzer-Weissmann and Lorraine Fraser,

  “British Vaccine Breakthrough Will Save Millions

  from Malaria,” The Telegraph, August 18, 2002

  A VACCINE TO PREVENT MALARIA is a wonderful idea that would save millions of lives, but it is the Holy Grail of tropical medicine. So far, no one has been able to find or attain it. Military labs, giant pharmaceuticals, and thousands of brilliant researchers have spent hundreds of millions of dollars and as many hours trying everything possible but have not yet succeeded in producing a vaccine that is safe, effective, and reliable. And even if a vaccine is discovered, there may always be children who slip between the cracks and don’t get it, allowing the parasite to live to fight another day.

  Even though—to date—it can’t be prevented by vaccine, malaria can be cured if treated in time. Doctors can only save people if they can diagnose the disease accurately and if they have access to needed medicines. Both are easier said than done in the developing world, where labs, equipment, and pharmacies are scarce. The drugs are still often too expensive for those who need them the most. And so, in a parallel universe to the vaccine development community, researchers also work on developing a drug that can be produced on a large scale at low cost.

  Three thousand miles from Steve Hoffman’s lab at Sanaria, on the opposite coast, Jay Keasling, a professor of chemical engineering at the University of California at Berkeley, is working to advance a medicinal cure instead of a vaccine. His strategy is based on a form of synthetic biology that could dramatically reduce the cost of malaria treatment. If either Hoffman or Keasling achieves a triumphant breakthrough, funds for the other could dry up. Which means that Hoffman is not only competing against other vaccine developers, but against Keasling and a large number of others in the medical establishment who believe that the more direct route to saving lives is through the proven track record of drugs. For many of them, a malaria vaccine represents nothing more than unfulfilled dreams that have little chance of becoming reality.

  A coworker of Keasling’s at Berkeley’s Lawrence Berkeley National Laboratory, Lynn Yarris, has put it bluntly: “The complex life-cycle of Plasmodium falciparum, the parasite that carries malaria, makes it impossible to eradicate the disease. Treatment is the only option and the most effective current treatment is artemisinin.”1

  Artemisinin is the one drug that remains effective against malaria strains that are now resistant to front-line drugs like chloroquine. The Chinese have been using it as an herbal remedy for more than 2,000 years, but it was the Vietnam War that provoked them to explore its properties regarding malaria. It has a nearly 100 percent success rate for all known strains of malaria, destroying the parasite by releasing high doses of oxygen-based free radicals that attack the parasite inside the iron-rich red blood cells. The controversies th
at surround the varying degrees of effectiveness of malaria vaccines in trial are not relevant to artemisinin. Artemisinin works (although indications of drug resistance have suggested the need to deliver it in the form of combination therapies with other drugs rather than by itself).

  It only came to the attention of Western researchers by chance in 1979, when Nick White, the director of the Southeast Asia office of The Wellcome Trust, one of the largest medical research foundations in the world, received a dog-eared copy of a paper from a Chinese medical journal from a friend in Hong Kong. It reported the results of clinical trials conducted by a team of scientists created by Chairman Mao for the express purpose of screening herbal remedies for a malaria cure. “Gobsmacked,” White arranged to visit the scientist who led the team, Professor Li Guo Qiao, and when he left that meeting, he had a bottle of artemisinin in his hands.2

  But artemisinin is not easy to get hold of. It is extracted from the dry leaves of the sweet wormwood tree, a six-foot-tall plant that can grow in many places but only produces artemisinin in the mangrove swamps of China and Vietnam. Not only is the plant rare, but the substance is difficult to extract, which makes it expensive. The process is labor intensive, sometimes involving diesel-fuel purification methods that can leave toxic impurities in the final drug product. There have been reports of speculators buying and hoarding the plants, quadrupling the price and making it even less accessible to those who need it. In the fall of 2005, prices went from $115 a pound to more than $400. By 2008, additional planting on the part of farmers had reduced the price to $70 a pound.3

  Still, the World Health Organization predicts that for the foreseeable future, demand for artemisinin will continue to greatly outpace supply. Keasling expects a shortfall of at least 100 million treatments in 2010 and 2011. Kent Campbell, director of the Malaria Control Program at PATH, underscored the stakes in an interview with The New Yorker: “Losing artemisinin would set us back years, if not decades. . . . One can envision any number of theoretical public-health disasters in the world. But this is not theoretical. This is real. Without artemisinin, millions of people could die.”4

  A course of treatment for adults, produced by Novartis, comes to about $2.40 per person. Novartis has already been accused of breaking commitments to supply sufficient amounts to meet projected demand. Médecins Sans Frontières, the international humanitarian organization also known as Doctors Without Borders, argues that the company is not interested in a market that is not profitable. In 2005, Novartis president Daniel Vasella, speaking to the Financial Times, said, “We have no model which would [meet] the need for new drugs in a sustainable way. You can’t expect a for-profit organisation to do this on a large scale.”5 He was referring to the lack of paying customers through which pharmaceutical firms could make back the investment necessary to produce sufficient quantities of the drug.

  Left to its own devices there is simply no way nature will produce enough of this critically needed and already proven cure. But Jay Keasling is quite as capable as Steve Hoffman of making a leap of imagination: “I see no reason why we can’t completely reimagine the chemical industry,” he told me.6 “With the tools of synthetic biology, we don’t have to just accept what nature has given us.” It’s a philosophy so bold as to border on hubris, but with a million kids a year dying from malaria, Keasling’s drive to find shortcuts is fueled by a sense of urgency. Keasling is using genomics to accelerate nature’s own processes and manipulate them to create more of the products we need.

  Keasling was raised on his family farm outside of Lincoln, Nebraska, and synthetic biology was unheard of when he took his first genetics class at the University of Nebraska in 1983. But by the time he reached the Ph.D. program at the University of Michigan, he “wanted to manipulate a cell like an engineer does a chip,” he told California magazine.7 Following a post-doc at Stanford, he arrived at UC Berkeley’s Department of Chemical Engineering in 1992 with some unique ideas about reengineering enzyme reactions within microbes.

  Just over ten years later, working from home just as Hoffman had, Keasling launched the biotech company Amyris to carry out those ideas. He has not left the institutional realm entirely, like Hoffman has. Instead, Keasling has deftly merged several roles, not only heading up Amyris Biotechnologies but also continuing to teach chemical engineering and bioengineering at UC Berkeley and serving as founding director of the Synthetic Biology Department at Berkeley, CEO of the Joint BioEnergy Institute, and acting deputy laboratory director of Lawrence Berkeley National Laboratory.

  Keasling aims to make it much cheaper to produce artemisinin, thereby bringing down the price and making it possible to treat the vast number of malaria victims who now go untreated. Speaking with a reporter from the UC Berkeley News in 2004, he explained how, saying, “We are designing the cell to be a chemical factory.” Like Hoffman, Keasling turned to business because he saw the potential for commercial enterprises to bring an idea to scale. Capitalized by a grant from the Gates Foundation, Amyris uses synthetic biology to isolate genes from their natural sources and insert them into industrial microbes, and thereby to produce natural compounds much more cheaply.8

  Keasling’s research team mixed different genes from different organisms to perform chemistry inside living cells. They combined genes from yeast and the wormwood plant with the common intestinal Escherichia coli bacteria cell to create a new metabolic pathway—a series of chemical reactions that occur within a cell—that yields a form of artemisinin called amorphadiene. Amorphadiene is an artemisinin precursor that is already used as the basis for all of the artemisinin drugs currently on the market. Keasling and his team believe they are on track to produce 10,000 times the amount possible by the old ways.

  Thus Keasling’s team encouraged the bacteria to produce molecules that are not found in sufficient quantities in nature. Metabolic engineering of microbes co-opts the microbes’ metabolism for our own benefit. It could replace the expensive techniques used in the chemical industry today—not just for making artemisinin, but for making a wide variety of other drugs that are badly needed but difficult to produce in the quantities needed around the world.

  Keasling believed the artemisinin he created in his lab could be sold for one-tenth of the price of what other producers were charging, meaning about 21 cents a dose. “We’re taking a natural product in short supply, using biotechnology to produce it and to produce it very inexpensively in the developing world,” he told me. Providing it to 70 percent of the malaria victims in Africa would cost about $1 billion.

  As different as Hoffman and Keasling may be in terms of their approaches to malaria, they both work at the intersection where science, philanthropy, and entrepreneurship are converging. They both are taking a known, effective solution and trying to make it affordable and sustainable. Their innovation is to produce it at a scale that drives down cost, and therefore price, and to do so by allowing nature (the mosquito, or the enzymes) to do the work rather than manufacturing it at great expense.

  Jay Keasling and Steve Hoffman have met only once, at a conference where they both happened to be giving a talk. Though they express genuine admiration for each other’s accomplishments, each is so focused that, even when prompted, neither shows much interest in the other. But when I first started visiting Keasling I could see that he was philosophically connected to Hoffman in ways beyond their shared commitment to ensuring that children didn’t die from malaria.

  The first thing Steve Hoffman told me on the first day we met was that the solution to a malaria vaccine was not a matter of scientific discovery but rather of biotech engineering. Though he was overstating the point, because science played a critical role at every stage of his effort, he was trying to convey that we knew what worked, but the challenge was whether we could scale it. In leading the effort to apply engineering principles to biology, Keasling demonstrated a nearly identical insight in terms of what it would take to make highly effective medicines available on a mass scale, the kind of scale that woul
d ensure that children like Alima were quickly cured.

  Both were producing their product in a place that literally seemed impossible right up until they did it: Hoffman using the insides of mosquitoes as his primary production facilities, and Keasling using cells as chemical factories. They not only managed to see what the naked eye could not, but also to imagine a possibility that no one else had imagined. Both were undeterred by either the complexity and unknowns inherent in such virgin territory or the skepticism of respected colleagues. The conviction that they could save lives offset the risks they would be taking.

  At the end of 2004, the Gates Foundation awarded a $42.6 million grant to support Keasling’s work through a partnership between UC Berkeley, Amyris, and the Institute for OneWorld Health, the nonprofit pharmaceutical created in 2000 to help develop drugs and vaccines for neglected diseases. Keasling’s responsibility was to do the research necessary for perfecting the microbial factory for artemisinin. Amyris would develop the process for industrial fermentation and commercialization. OneWorld Health would handle the regulatory work.

  It was expected to take five to ten years to develop the microbes into truly large-scale producers of the artemisinin precursor. Keasling also hoped to produce promising anti-AIDS drugs and cancer-fighting medicines like Taxol using the same processes.

  A CHANCE TO SAVE THE WORLD—TWICE!

  The offices of Amyris overflow like a lab flask that can’t contain the chemical reaction within.

  The firm spills across a courtyard into a second building at the edge of Emeryville, California, near Oakland. There are nearly a hundred staff members, including biologists, chemists, and newly hired administrators and project managers.

  Producing an inexpensive antimalaria drug is not the only project that consumes their attention. Amyris takes aim at another, very different global challenge as well, and it exploits the same pioneering technology. Close on the heels of the effort to create synthetic artemisinin, and in danger of overtaking it, is the effort to produce synthetic fuels. If the project is successful, it could reduce our dependence on oil and mitigate global warming.