The code breaker, p.11
The Code Breaker, page 11
It was the beginning of a new aspect of her career: looking for ways to turn her CRISPR discoveries into tools that could be useful in medicine. Haurwitz took the idea one more step. If Cas6 could be turned into a medical tool, it could become the basis for a company. “Once we understood how the Cas6 protein worked,” she says, “we started to get some ideas on how we might steal it from bacteria and repurpose it for our own uses.”1
For much of the twentieth century, most new drugs were based on chemical advances. But the launch of Genentech in 1976 shifted the focus of commercialization from chemistry to biotechnology, which involves the manipulation of living cells, often through genetic engineering, to devise new medical treatments. Genentech became the model for commercializing biotech discoveries: scientists and venture capitalists raised capital by divvying up equity stakes, then they entered into agreements with major pharmaceutical companies to license, manufacture, and market some of their discoveries.
Thus did biotech follow the path of digital technology in blurring the lines between academic research and business. This fusion in the digital realm began right after World War II, mainly around Stanford. With prodding from its provost Frederick Terman, Stanford professors were encouraged to turn their discoveries into startups. The companies that sprang out of Stanford included Litton Industries, Varian Associates, and Hewlett-Packard, followed by Sun Microsystems and Google. The process helped turn a valley of apricot orchards into Silicon Valley.
During this period, many other universities, including Harvard and Berkeley, decided it was more appropriate to stick to basic scientific research. Their traditional professors and provosts disdained commercial entanglement. But after envying Stanford’s success in the realms of infotech and then biotech, they began to embrace entrepreneurship. Researchers were encouraged to patent their discoveries, partner with venture capitalists, and create businesses. “These companies frequently maintain their links with the universities, working closely with faculty members and postdoctoral candidates on research projects, and sometimes using the university laboratories,” Harvard Business School professor Gary Pisano wrote. “In many instances, the founding scientists even retain their faculty posts.”2 This would become Doudna’s approach.
Startup
Until then, Doudna had never thought much about commercialization. Money was not then, nor would it be later, a primary motivation in her life. She and Jamie and Andy lived in a spacious but not lavish house in Berkeley, and she never had the desire for a grander one. But she did like the idea of being part of a business, especially one that could have a direct impact on people’s health. And unlike Genentech, a startup would have no corporate politics, nor would it drag her away from academia.
Haurwitz likewise felt the allure of business. Although she was good at the lab bench, she realized that she was not cut out to be an academic researcher. So she began taking courses at Berkeley’s Haas School of Business. Her favorite was one taught by the venture capitalist Larry Lasky. He split his class into teams of six, half business students and the other half science researchers. Each team built a series of decks for a fictional biotech startup and then spent the semester perfecting how they would pitch it to investors. She also took a class from Jessica Hoover, who had been head of business development at a biotech firm that studied ways to commercialize medical products, including how to secure and license patents.
During Haurwitz’s final year in her lab, Doudna asked what she wanted to do next. “Run a biotech company,” Haurwitz replied. That would have been an unsurprising response at Stanford, where commercializing research was celebrated, but it was the first time Doudna had heard such an answer at Berkeley, where most PhD students aimed for an academic career.
A few days later, she went into the lab to find Haurwitz. “I’ve been thinking that maybe we ought to start a company around using Cas6 and some of the other CRISPR enzymes as a tool,” she said. With no hesitation, Haurwitz responded, “Of course we should.”3
So they did. The company was founded in October 2011, and it remained based in Doudna’s academic lab for a year while Haurwitz finished her studies. After she got her PhD in the spring of 2012, she became the president and Doudna the chief scientific advisor of the fledgling endeavor.
The idea was that the company, which moved into a low-slung space in a nearby strip mall, would commercialize the patents related to the Cas6 structure and eventually other discoveries to come out of Doudna’s lab. Their initial aim was to turn Cas6 into a diagnostic tool that clinics could use to detect the presence of viruses in humans.
The company
By the time Doudna and Haurwitz started their company in 2011, Berkeley had become savvier about encouraging its researchers to be more entrepreneurial. It launched a variety of programs to nurture startups formed by its students and professors. One of them, which was formed in 2000 in partnership with the other University of California campuses in the Bay Area, was the California Institute for Quantitative Biosciences (QB3), which had as its goal “a catalytic partnership between university research and private industry.” Doudna and Haurwitz were selected to become participants in QB3’s Startup in a Box program, which gave training, legal advice, and banking services to scientist-entrepreneurs who wanted to turn their basic discoveries into commercial ventures.
One day Doudna and Haurwitz took the subway into San Francisco to meet with the lawyer who Startup in a Box enlisted to help them incorporate their new company. When he asked for its name Haurwitz said, “I’ve been talking to my boyfriend about it, and we think we should call it Caribou.” The name is a cut-and-splice mash-up of “Cas” and “ribonucleotides,” which are the building blocks of RNA and DNA.
Haurwitz had talents not often found in Silicon Valley entrepreneurs. With her steady personality, she was a naturally good manager. She was down to earth, unflappable, practical, and straightforward. There was no whiff of the combination of ego and insecurity exuded by many startup CEOs. She did not exaggerate or overpromise. That offered many advantages, one of which was that people tended to underestimate her.
On the other hand, she had never been a CEO, so she had some learning to do. That led her to join a local professional development group for young CEOs, the Alliance of Chief Executives, which met for a half-day each month to share problems and solutions. It’s hard to imagine Steve Jobs or Mark Zuckerberg joining such a support group, but Haurwitz, like her mentor Doudna, had a self-awareness and humility not usually found among alpha males. Among other things, her Alliance group coached her on how to create a team with different types of expertise.
Today the mere appearance of the word CRISPR in a prospectus is enough to cause venture capitalists to go into heat. But when Doudna and Haurwitz tried to raise money, they had little luck. “At that time, the topic of molecular diagnostics was a turnoff to venture capitalists,” Doudna says. “I also feel that there is an anti-female undercurrent, and I was worried that if we took venture money, that Rachel might be pushed out as CEO.” None of the venture capitalists they met with was a woman, and this was in 2012. So instead of continuing to seek venture money, they decided to raise what they could from friends and family. Both Doudna and Haurwitz put in their own money.
The triangle
Its bootstrap success may, on the surface, make Caribou Biosciences seem like a poster child for pure free-market capitalism. And there was, nicely, an element of that. But it’s important to look deeper and see how, as in so many other companies, from Intel to Google, innovation has been a product of a distinctively American mix of catalysts.
As World War II was ending, the great engineer and public official Vannevar Bush argued that America’s innovation engine would require a three-way partnership of government, business, and academia. He was uniquely qualified to envision that triangle, because he had a foot in all three camps. He had been dean of engineering at MIT, a founder of Raytheon, and the chief government science administrator overseeing, among other projects, the building of the atom bomb.4
Bush’s recommendation was that government should not build big research labs of its own, as it had done with the atomic bomb project, but instead should fund research at universities and corporate labs. This government-business-university partnership produced the great innovations that propelled the U.S. economy in the postwar period, including transistors, microchips, computers, graphical user interfaces, GPS, lasers, the internet, and search engines.
Caribou was an example of this approach. Berkeley, a public university with private philanthropic supporters, housed Doudna’s lab and had a partnership with the federally funded Lawrence Berkeley National Laboratory. The amount of federal grants that went from the National Institutes of Health (NIH) to Berkeley to support Doudna’s research into CRISPR-Cas systems was $1.3 million.5 In addition, Caribou itself was able to get a federal grant from the NIH’s small business innovation program, which provided $159,000 to the company to create kits to analyze RNA-protein complexes. The program was designed to help innovators turn basic research into commercial products. It kept Caribou alive during the early years, when venture funding was not forthcoming.6
There is one other element that is now often added to the academic-government-business triad: philanthropic foundations. In the case of Caribou, that came as a grant from the Bill and Melinda Gates Foundation, which provided $100,000 to fund work on using Cas6 as a tool to diagnose viral infections. “We plan on creating a suite of enzymes that specifically recognize RNA sequences characteristic of viruses including HIV, hepatitis C and influenza,” Doudna wrote in her proposal to the foundation. It was a prelude to the funding Doudna would receive from Gates in 2020 to use CRISPR systems to detect coronaviruses.7
CHAPTER 16 Emmanuelle Charpentier
The wanderer
Conferences can have consequences. While attending one in Puerto Rico in the spring of 2011, Doudna had a chance meeting with Emmanuelle Charpentier, an itinerant French biologist who had an alluring mix of mystery and Parisian insouciance. She, too, had been studying CRISPR, and she had homed in on the CRISPR-associated enzyme known as Cas9.
Guarded but engaging, Charpentier was a woman of many cities, many labs, many degrees and postdoc programs, but few roots and commitments, ever willing to pack up her pipettes and move, never showing any outward signs of worry or an instinct for competition. This made her much different from Doudna, which is perhaps why they bonded at first, although mainly in a scientific rather than emotional way. They both had warm smiles that made their protective shells almost, but not totally, invisible.
Charpentier grew up in a leafy suburb on the Seine south of Paris. Her father was in charge of the neighborhood park system, and her mother was the administrative nurse in a psychiatric hospital. One day when Charpentier was twelve, she walked past the Pasteur Institute, the Paris research center specializing in infectious diseases. “I am going to work there when I grow up,” she told her mother. A few years later, when she had to designate a field for her baccalauréat exam, which determines a student’s course of study in college, she chose life science.1
Emmanuelle Charpentier
She also was interested in the arts. She took piano lessons from a neighbor who was a concert musician and pursued ballet with the possibility that she might become a professional dancer, continuing her training well into her twenties. “I would like to have been a ballet dancer, but I finally realized that would be too risky as a career,” she says. “I was a few centimeters too short and I had a ligament problem that affected the extension of my right leg.”2
There were lessons from the arts, she would discover, that applied to science. “Methodology is important in both,” she says. “You also must know the basics and master the methods. That requires persistence—repeating experiments and repeating them again, perfecting how to prepare the DNA when you clone a gene, and then doing it over and over again. It’s part of the training, just like the hard work of a ballet dancer, repeating all day long the same moves and methods.” Also like the arts, once a scientist masters the basic routine, she has to combine it with creativity. “You have to be rigorous and disciplined,” Charpentier explains, “but also know when to let yourself loose and blend in a creative approach. I found in biological research the right combination of persistence and creativity.”
* * *
Fulfilling the prediction she made to her mother, she pursued her graduate studies at the Pasteur Institute, where she learned how bacteria can become resistant to antibiotics. She felt at home in the lab. It was a quiet temple for individual persistence and contemplation. She could be creative and independent as she pursued a path toward her own discoveries. “I began to see myself as a scientist and not just as a student,” she says. “I wanted to create knowledge, not just learn it.”
Charpentier became a postdoctoral pilgrim, enrolling at Rockefeller University in Manhattan in the lab of the microbiologist Elaine Tuomanen, who was studying how the bacteria that cause pneumonia have DNA sequences that can shift, making the bacteria resistant to antibiotics. On the day she arrived, Charpentier found out that Tuomanen was moving, along with her lab and its postdocs, to the St. Jude Children’s Research Hospital in Memphis. There Charpentier worked with Rodger Novak, another postdoc in Tuomanen’s lab, and he became for a while a romantic companion and then a business partner. While in Memphis, they coauthored with Tuomanen an important study that showed how antibiotics such as penicillin trigger suicidal enzymes in bacteria that dissolve their cell walls.3
Charpentier’s peripatetic mind and spirit made her ever ready to move to new towns and new topics, and this was hastened by an unpleasant biological discovery she made in Memphis: Mississippi River mosquitoes love French blood. In addition, she wanted to shift her focus from single-cell microbes such as bacteria and learn about genes in mammals, mainly mice. So she switched to a lab at New York University, where she produced a paper on ways to manipulate mouse genes to regulate hair growth. She also did a third postdoc in which she, along with Novak, focused on the role of small RNA molecules in regulating gene expression in Streptococcus pyogenes, a bacteria that causes skin infections and strep throat.4
After six years in the U.S., she moved back to Europe in 2002 to become the head of a microbiology and genetics lab at the University of Vienna. But once again she became restless. “People in Vienna knew each other a bit too well,” she says, which she clearly regarded as a drawback rather than a benefit. “The dynamics got a bit stuck and the structures became inhibiting.” So by the time she met Doudna in 2011, she had left behind most of the researchers in her lab to relocate on her own to Umeå, in northern Sweden. Umeå was no Vienna. Four hundred miles north of Stockholm, the town’s 1960s-built university consisted of a cluster of modernist buildings on land that had been a grazing ground for reindeer herders. It was best known for its research on trees. “Yes, it was a risky move,” Charpentier agrees, “but it gave me a chance to think.”
* * *
In the years since she entered the Pasteur Institute in 1992, Charpentier had worked in ten institutions in seven cities in five countries. Her nomadic life reflected the fact, and reinforced the fact, that she resisted bonds. With no spouse or family, she sought out changing environments and adapted to them without any inhibiting personal ties. “I enjoy the freedom of being on my own, of not depending on partnership,” she says. She hated the phrase “work-life balance” because it implied that work competes with life. Her work in the lab and her “passion for science,” she says, brought her a “happiness that is as fulfilling as any other passion.”
Like the organisms she studied, her need to adapt to new environments kept her innovative. “My instinct to keep moving can be destabilizing, but that can be good,” she says. “It assures that you never get stuck.” Going from one place to another was her way of repeatedly reconsidering her research and forcing herself to start fresh. “The more one moves, the more one learns to analyze as a new situation and see things that others who have been in the system a long time have not identified.”
Moving also made her feel like a bit of a foreigner most of the time, the way the young Jennifer Doudna felt as a child in Hawaii. “It’s important to know how to be an outsider,” Charpentier says. “You’re never completely at home, and that can drive you. It can challenge you not to seek being comfortable.” As with so many other observant and creative people, she found that a sense of detachment or slight alienation made her better at figuring out the forces at play. That helped her honor the maxim often preached by Louis Pasteur himself: Be prepared for the unexpected.
Partly as a result, Charpentier became one of those scientists who could be both focused and distracted. Though impeccably groomed and casually elegant even when riding a bicycle, she also fit the stereotype of an absent-minded professor. When I traveled to see her in Berlin, where she moved after Umeå, she got to my hotel on her bike a few minutes late. It turned out that she had come that morning from a visit to Munich, and when she was leaving the station she realized that she had left her luggage on the train. Somehow she caught up with the train at its terminal, retrieved her luggage, and then biked to my hotel. As we walked to her nearby lab at the Max Planck Institute for Infectious Diseases, on the grounds of Charité, the venerable teaching hospital in the middle of Berlin, she pushed her bike purposely down a main artery until, after a few blocks, she realized that she had led us in the wrong direction. The next day, when a friend and I took her to see a show at an art museum, she managed to lose her admission ticket between the box office and the main entrance, and when we went to a serene Japanese restaurant for dinner, she left her phone behind. Yet when we were sitting in her lab office or over a multicourse sushi meal, she could speak for hours with super-intense focus.
