The Imaginations of Unreasonable Men

by Bill Shore

  Keasling’s insight, simple in concept but extraordinarily complex in the lab, is that rare and valuable plant-based substances could be grown in lab tanks. All you have to do is transplant genes from the plant into fast-growing bacteria like E. coli and yeast. The insight has a lot of different applications, most of which are related to medical cures. But, theoretically, it could also be used to produce a next generation of carbon-neutral biofuels.

  Amyris’s founding partners, while motivated by a desire to help malaria victims, were also savvy enough to appreciate the potential for enormous profit that lay in the field of synthetic biology and the processes they were perfecting. But what animated their conversation and sustained absurdly long hours in the lab was the thrill of basic science: the prospect of discovering something never before known, of peeking behind nature’s curtain to get a glimpse of the universe’s secrets, of making real to others what once they alone imagined.

  Jack Newman is the forty-something vice president of Amyris overseeing lab research. The son of peripatetic artists, he dropped out of high school at fourteen. By his fifteenth birthday, he was attending community college, and en route to a degree at UC Berkeley in molecular and cellular biology. Pursuing a doctorate at the University of Wisconsin, Newman heard Keasling guest-lecture and determined to do his postdoctoral work in Keasling’s lab

  “My life is a movie,” Newman told me. “Even I can’t believe it turned out the way it did. Amyris is exactly the company that I wanted to work for from the time I was fourteen. It is everything I imagined and I’ve never wanted to do anything else. It is exactly that company in every way.”

  In black jeans and a black T-shirt, with long black hair flowing behind a prominent forehead and beyond his shoulders, he looks more rock band or computer geek than Dr. Newman. Some of the company’s energy seems bottled up inside his body, which moves in awkward ways, his head occasionally tilting then snapping back. A natural teacher whose enthusiasm is infectious, he jumped up to the white board to diagram for me their process of using chemistry to create amorphadiene and artemisininc acid.

  “The chemistry isn’t simple, but it is reliable,” Newman said. “You get an outcome you can count on. Biologic processes don’t work that way. Historically biology was too complex to apply engineering to, but that is changing.” Ever faster genome sequencing has made it so.

  At the time I visited Amyris, the milestones that Amyris, Keasling’s lab, and the Institute for OneWorld Health had agreed to with the Gates Foundation focused on getting the metabolically engineered microbe to produce artemisinin on the scale of 25 grams per liter. At first they were getting 0.0000000001 gram per liter. Twenty-five grams per liter would be far more than has ever been produced in a lab, and a telling indicator of future potential. They’ve been testing both yeast and E. coli. “Both crossed the finish line,” said Newman of the ability of yeast and E. coli to grow large-scale batches of the drug. “Just this morning an experiment on this came back with results that were beautiful.”

  Newman didn’t use “beautiful,” to mean “great” or “cool.” He meant beautiful the way it is used to describe a Monet or a Matisse: elegant, balanced, pleasing to the senses. He looks at chemical analysis and sees art. The 25-gram mark had not yet been reached, but things looked very promising.

  Keasling walked me through room after room of tubes, tanks, coils, and monitors, most of it connected to enormous computing power, young technicians, some with arms covered in tattoos from wrist to shoulder, strove to create artemisinin in ever greater quantities.

  Just as Steve Hoffman would wrestle with whether what worked via the bite of the mosquito would work when scaled into a clinical manufacturing process, Amyris faced the issue of whether what worked in the shake flask on a lab shelf would work in a 50,000-liter tank the size of a bus. Scale changes chemistry. For example, the pressure at the bottom of the tank is different from the pressure at the top. That alone can completely alter results. And there are different surface-to-mass ratios, which vary with exposure to oxygen.

  Amyris’s president, Kinkead Reiling, fell in love with math and science at a young age. In blue jeans and a button-down striped shirt with a neatly trimmed goatee, he seemed like an earnest, cautious person. His eyes lit up as he described a protein that, if pulled taut, would be like a long string of spaghetti, and when let go would fold up and in on itself.

  Reiling, a military brat whose father flew cargo planes for the U.S. Air Force, started out in physics at the University of California at Los Angeles, fascinated by the notion of being able to understand the world by understanding the most basic parts of which it is made. He switched to biology at Columbia University and had the chance to work with Professor Robert Stroud, whose legacy was great advances in protein crystallography. He’s been a jack-of-all-trades at Amyris, reluctantly moving farther from the science to assume business responsibilities for which he has no training. Finances, office space, human resources, hiring, payroll—all of this is Reiling’s portfolio. Akin to the oldest child in a dysfunctional family, he had to be the responsible one.

  An added undercurrent of complexity runs through this company because its investors have varying expectations and objectives, even though their interests may be aligned. When Bill Gates funded Amyris to develop artemisinin, there existed essentially no commercial market or likelihood of financial gain. But in 2006, venture capitalists Kleiner Perkins and Khosla Ventures put $20 million into Amyris and arranged for John Melo, former head of fuel operations for BP, to become president. Shortly thereafter BP committed to invest $500 million over ten years into a new Biosciences Energy Institute at UC Berkeley. BP, looking ahead to whatever might end up being the next generation’s source of energy, apparently sees the potential for profit in the development of an alternative to fossil-fuel extraction.

  Keasling has little time for what goes on outside of Amyris. At a 2007 Harvard School of Public Health conference at which he presented, he encountered—but did not really meet—“the vaccine guys.” He not only doesn’t know Steve Hoffman from Sanaria and Rip Ballou from GlaxoSmithKline, but doesn’t seem to focus much on what they are up to. They are the other side of the ideological wall: the hopeless idealists pursuing a total victory over malaria while losing countless small wars in the meantime. Keasling is busy fighting the small wars: “They’ve been at it for fifty years and there has still never been a vaccine to reach the market, while meanwhile millions of kids die each year. So we better get some medicines to those kids.”

  His schedule could compete with that of any other driven person I’ve ever met: “I wake up every morning at 4:30, it’s the most magical time of the day, and I go to the gym from 5 to 7. Then I’m at Berkeley, teaching.” He has about fifty students. “And in the afternoon I get over to the lab, and a couple days a week to Amyris. There is some complaining about not being able to get on my schedule, but I don’t want things on my schedule.”

  He said teaching is the most important thing he does, but also admitted, with a somewhat pained expression, that he may not be teaching forever. It depends on the grants he gets.

  Describing the decision to take VC money and then BP’s investment, and what it meant to give up control, he was clear: “If the question is, Do you want to own 100 percent of zero, or 20 percent of something really big, I know what I want.”

  Everyone I spoke with at Amyris sounded a bit defensive about the dual mission of combating malaria and inventing biofuels, but they all also went out of their way to praise John Melo, who came in as Amyris’s CEO after a career at BP and Amoco. Reiling described him as “the least oily oil guy” he knew. “He really gets what we’re doing. Doesn’t totally understand the science, but respects it.” And he also made the point that all interests are aligned. “Amyris only works if our work with artemisinin is a success,” Reiling said.

  Both Keasling and Amyris were in discussions with the U.S. Department of Energy about grants that would further their work. And like Hoffman at San
aria, Keasling’s team was giving some thought, even though it is technically beyond their sphere of influence, to how the medicine will actually be distributed in Africa. “Everyone here is motivated by seeing the science actually used,” Keasling told me.

  The example of Amyris makes a compelling case for nonprofits embracing the disciplines of science rather than fixating only on the need for MBAs to secure the “entrepreneurial” label. The team at Amyris is trying to solve almost unimaginably complex social problems through biotech engineering. They are trying to scale up proven solutions and to lower their cost.

  Scientists bring proof and precision to their efforts. Clinical trials guarantee predictable results. By March 2008, Amyris had formed a new partnership with Sanofi-Aventis, a leading pharmaceutical company based in France. Achieving the goal of mass-producing low-cost, microbial-based artemisinin would require greater fermentation capacity, and Sanofi could provide that capacity. Less than a year later, in February 2009, Amyris published an article announcing the achievement of their milestone: the production of 25 grams per liter of amorphadiene through E. coli fermentations, proof that commercially viable levels of artemisinin could be produced through Keasling’s process.9 And Keasling intends to continue to explore strategies for increasing the yield.

  It’s hard to imagine anything more valuable than a new medicine that would save the lives of more than 1 million children a year. But what about the new model that led to that medicine? It is the model itself, combining science, philanthropy, and market economics, that may prove to be the lasting legacy of both Keasling and Hoffman. What’s more important than the fact that they may succeed in developing ways to cure or prevent malaria—as important as that is—is that they have eliminated the market gaps that so often undermine social solutions.

  HITTING THE HIGH NOTES

  It is no accident that both Jay Keasling and Steve Hoffman have worked closely with and been funded by an innovative organization called the Institute for OneWorld Health. Founded in 2000, it is the world’s first and only nonprofit pharmaceutical. It is also a mechanism for market making. In some cases, it finds drugs whose patents have expired. In others, it gets pharmaceutical companies to donate the intellectual property from research and development efforts for drugs they’ve abandoned because they lack the potential for profit. Either way, OneWorld Health aims to pick up the pieces, produce the drugs at relatively low cost, and make them available to the world’s poor. Since OneWorld Health doesn’t need to make a profit, it can concentrate on fulfilling a mission that is purely altruistic.

  The nonprofit pharmaceutical was the idea of Victoria Hale, forty-nine, who, with a Ph.D. in pharmaceutical chemistry, worked at the Food and Drug Administration’s Center for Drug Evaluation and Research for four years at the beginning of her career. Shortly before Steve Hoffman left the navy to get business experience at Celera, Hale left the government to do the same at a biotechnology firm called Genentech. She used that experience to start Institute for OneWorld Health in 2000. Like both Hoffman and Keasling, she knew that the effective medical solutions were out there, but that they weren’t being manufactured and distributed at the necessary scale.

  In launching the Institute for OneWorld Health, Hale faced the kind of challenges inherent in reimagining something as established as the pharmaceutical industry. She recalled for the Chronicle of Philanthropy that it took ten months for the IRS to grant OneWorld’s nonprofit status: “There was no precedent for them to comprehend the concept of a nonprofit pharmaceutical company until we offered the analogy of public versus commercial television . . . which serve different audiences, provide different products, and are funded differently.”10

  In October 2007, Hale and Keasling spoke at the annual PopTech conference in Camden, Maine, on a panel called “Changing the Paradigm.” Notwithstanding the overused cliché, it was a significant and telling title. The focus was not on malaria or science but on new ways of thinking to solve seemingly unsolvable problems.

  The audience did not have global health, tropical disease, or malaria eradication on their agenda. People who attend PopTech come from a wide variety of fields and are bound together only by an interest in the trends shaping the future. The chemistry and biology that dominated Keasling’s and Hale’s working hours were complex for the layman and almost impossible to present or summarize. But not so the expansive thinking, leaps of imagination, and collaborative partnerships they had brought to their work. Those had applicability to a wide range of issues and were relevant to the large and diverse audience.

  Hale and Keasling had just flown directly from the Malaria Forum in Seattle hosted by the Bill and Melinda Gates Foundation. I watched them on a live video streaming that PopTech offers. Victoria Hale began, as I’d seen her do many times before, with a few images on slides—a typical Indian village with a high incidence of visceral leishmaniasis, a parasitic disease also known as black fever that kills hundreds of thousands a year. Hale paused on a slide of women and children, some of whom had red hair due to nutritional deficiencies. She described them as “invisible people in our world, voiceless, and many are women, which means really voiceless.”

  The black fever parasite is spread by the bite of a sand fly. The parasite goes into the bone marrow and suppresses white cells. The cure costs $300 but the average income in Bihar in eastern India is 30 cents a day. The Institute for OneWorld Health also works on malaria and diarrhea, currently in India, Bangladesh, and Nepal, but soon in Sudan and Brazil as well.

  Hale went onto describe her own “personal journey, which began at the FDA.” She said, “I was at the FDA for five years. It was a fabulous job. And then I was at Genentech and had a fabulous time, until one day I wasn’t having fun anymore and resigned.”

  “I wanted quiet and to settle the confusion in my mind,” Hale recalled. “Genentech was developing great medicines but for fewer and fewer people. Biotech products are very expensive. I felt this combination of pride in the talents of all those I worked with and shame that as an industry we weren’t doing all we could. If you know that more could be done, how can you not do it?”

  The problem, as she saw it, was that “only the pharmaceutical industry knows how to make new medicines. The industry had to be engaged.” “So I designed an experiment to see if a pharmaceutical company could be driven not by profit but by venture philanthropy,” explained Hale, referring to a type of philanthropy in which donors act like venture capitalists, investing in an enterprise’s team and capacity, and establishing specific benchmarks that must be met for further investment. “We wanted to see what happened if we took out that one variable, profit. Our proof of concept, finally, was with a drug for visceral leishmaniasis that we got down to $10 a dose.”

  Hale is a scientist who recognizes the limitations of science. She emphasized that “the obstacles are not technological but human obstacles: lack of will, political challenges, competing priorities, not making a decision to commit. My end goal was to bring the industry back to diseases of poverty, to bring the industry back to where it once was, and to where many of the employees of the pharmaceutical industry want it to be.”

  In talking about those without a voice, Hale found hers. She often is asked to speak about drug development, social entrepreneurship, philanthropy, or corporate social responsibility. But more and more she brings the conversation back to “diseases of poverty,” to those who have no voice, and to the choices we can make or not make to help them.

  After the Q&A session, Hale closed by saying, “Technology is the easy part. The difficult part is after you have the technology. If you didn’t begin with thought about who the technology should impact, it will be mismatched.”

  She is well on the way to proving that her idea can work: “We knew there were people who worked at pharmaceuticals who would want to help, but we had no idea there would be so many and at every level,” Hale said. “Most of them got into the field to save lives and then found that many years later they were part of an ef
fort to help a large corporation make more money. We give them an opportunity to get back to that original impulse.”

  As she told the journal Nature, “There is a growing appreciation that a lot of IP [intellectual property] exists that many people—the discoverers, the owners, the people in the world who are in need—all agree should be moved into the public domain, but there’s nowhere for it to go. So, let’s put it in this non-profit sector and see what happens.”11

  The OneWorld Institute’s first successful drug was an antibiotic called paromomycin for visceral leishmaniasis, which won regulatory approval from the government of India on August 31, 2006. If it is the success Hale anticipates, a new industry will likely be born.

  Though OneWorld Health is a nonprofit, Hale had to make decisions with the discipline of a business executive accountable for returns on investment. “We need to ask whether anyone has the will to distribute a particular drug if we developed it today,” she told the PopTech audience. “For instance, and it’s painful to say this, we believe that developing a drug for sleeping sickness is just not an area on which we should spend our energy right now, because the countries in which sleeping sickness is an issue are at civil war and aren’t spending on public health.”

  Two of the relationships that Hale has built are with Keasling and Hoffman. In 2004, the Institute for OneWorld Health received a $43 million grant from the Bill and Melinda Gates Foundation to create a three-way partnership between the Institute for OneWorld Health, UC Berkeley, and Amyris Biotechnologies to significantly reduce the cost of artemisinin. She first visited Steve Hoffman when he was still at Celera, seeking advice and funding, and later she helped lay the foundation for the investment that the Gates Foundation made in Sanaria via the PATH Malaria Vaccine Initiative.