In autumn 1999, at the ripe old age of twenty-six, Liu joined the ranks of Harvard’s illustrious chemistry faculty, with its seven Nobel Prizes since 1964. Having demonstrated the possibilities of performing molecular evolution on the building blocks of life, Liu decided to go for something really big: protein evolution in a test tube. During his first decade at Harvard, Liu’s lab made a name in building new technologies for molecular evolution and applying them to treat human disease. The key method is called phage-assisted continuous evolution (PACE), developed by Kevin Esvelt.5 In 1999, Liu even dabbled in a type of genome editing—an effort to construct a gene activator made up of a DNA (or RNA) triple helix that could be targeted to various sites in the genome to regulate genes or cut DNA. Liu admits the project “utterly failed” but even though he moved productively into other areas of research, his interest in performing chemistry on the genome stuck.6
To lure the top students, competing against some of the biggest names in chemistry like Schreiber, Szostak, and Whitesides, Liu promoted his annual lab open house with eye-catching posters. One showed Liu metamorphosizing into Regis Philbin, the host of Who Wants to Be a Millionaire? Others showed him in full Matrix regalia or dressed up as Spider-Man villain Doctor Octopus. The strategy apparently worked: Liu’s research took off and in 2005, he was promoted to full professor, just thirty-one years of age. That same year, he joined Doudna as one of about three hundred investigators appointed (and technically employed) by the Howard Hughes Medical Institute, one of the highest echelons in American biomedical research.
For all of Liu’s brilliance and commitment in the lab, he strives to maintain a healthy work-life balance. “Chemistry is life, but life is a lot more than chemistry,” he says.7 Some of his hobbies hearken back to his engineering upbringing. In the early 2000s, he built a featherweight airplane that could almost hover indoors, before drones became a phenomenon. He also built a Lego robot called the mousapult, which would entertain his cats by throwing a toy in the direction of a heat signature, using a sensor from a burglar alarm.
Liu’s most intense—and lucrative—hobby, first picked up during his student years, was blackjack. His mathematical ability to count cards (a legal activity) became a teachable moment and something bordering on an obsession. Liu started teaching a weekly course for enthusiastic students from which he cultivated a devoted squad of fourteen “blackjack ninjas.” Every few months, the young professor would lead a delegation to Las Vegas and spend the weekend gambling—sometimes running fifteen hours at a time. Liu joked he was just hoping to earn enough to buy his wife a nice pair of earrings, but his posse was known to win “absurd sums of money.”8
On Sunday nights, Liu took the JetBlue red-eye flight from Las Vegas to Boston, rolling up to teach his morning chemistry lecture pretty tired. He would ask himself why he was flying to casinos to gamble with students.9 Occasionally though, after a particularly successful trip, he wondered if being a chemistry professor was all it was cracked up to be. Eventually, his hand was forced: the MGM Grand Casino in Las Vegas banned him. But he still carries a laminated card of calculations in his wallet should opportunity knock.
In his office on the third floor of the Broad Institute, besides Liu’s own art, skilled photography, and mineral collection, a visitor cannot help but notice the thirty-pound, three-foot Iron Man “Hulkbuster” replica. It’s the perfect metaphor: the ultimate shield to protect against the excesses of the Hulk’s gamma-ray-induced rampages. Like Tony Stark, Liu has a penchant for inventing cool technologies to shield humans against genetic mutations, stacking the odds and seeing how high he can fly. “He’s going to be the godfather of CRISPR 2.0,” says Gerald Joyce, director of the Genomics Institute of the Novartis Research Foundation.10 After listening to a spellbinding lecture from Liu in the Canadian Rockies in early 2020, a scientist sitting next to me whispered in my ear: “He’s a genius!”
Growing up in upstate New York, Nicole Gaudelli’s love of science and nature was nurtured by her father and grandfather. She loved going to zoos, fishing, growing crystals, and building water rockets. She thought about being a doctor, but her father suggested that she could help many more people by being a research scientist. During her PhD at Johns Hopkins, Gaudelli was captivated by a guest seminar given by Liu talking about PACE and molecular evolution. She decided to apply for a coveted position in Liu’s lab for her postdoc.
Shortly after Gaudelli arrived in the lab in 2014, she befriended a new postdoc from southern California who had just earned her PhD from Caltech. Alexis Komor was working on something completely different—a project inspired by months of email exchanges with Liu prior to her arrival. Komor had interviewed with Liu eighteen months before finishing her PhD, hoping to persuade a big-name chemist that she could flourish in his group.
Komor began emailing Liu ideas for her postdoc project (“mutually guided brainstorming” is how Liu puts it). One item was an idea she’d sketched out to fulfill a Caltech graduation requirement: she wanted to evolve a ribonuclease enzyme in the lab so that it could degrade a specific sequence of RNA. Liu liked it but suggested she think about DNA-based editors, in particular the CRISPR-associated nuclease, Cas9. On November 1, 2013, he emailed her: “If you could program a specific A-to-G (for example) change in the human genome, you could really transform genome engineering and possibly human therapeutics.”
Komor was excited but confused. “Why is he so crazy about this Cas9 thing?!” she thought.11 But she kept refining her idea and by the time she arrived in Boston in September 2014, the basic idea of base editing had been born. Ironically, Liu had confused Komor and Gaudelli in the run-up to their arrival, mixing up their respective project ideas. On Komor’s first day, Liu introduced her to the rest of the male-dominated lab, and then Gaudelli. “This is Nicole. I kept confusing you. You can see why!” The pair burst out laughing: Gaudelli has dark hair and eyes, unmistakable Italian heritage. Komor is quintessential Californian, blond hair and blue eyes. They became fast friends.
Komor’s first six months were uncomfortable, far apart from her husband who was still in California finishing his PhD. She hoped Boston would be a short-term stay to complete a postdoc so she could return to her family and the California sunshine. “Technology development projects are super risky,” she told me. “At the beginning I didn’t know what I was doing!” Group meetings in which her plans were microdissected by quizzical, sometime skeptical colleagues, were the bane of her existence.
Although Doudna was a classical chemist, the field of CRISPR genome editing had evolved as a largely biological discipline. Komor and Liu brought a different skill set, and it paid off. “Single-stranded DNA is a lot more reactive than when it is double-stranded,” Komor says. When Cas9 binds to DNA, it unzips the double helix to expose a stretch of about five bases of single-stranded DNA. Here, then, was a window to perform some cool chemistry. Komor began with cytidine deaminase, an enzyme that converts cytidine (C) to uracil (U), but only works on single-stranded DNA. By tethering the deaminase to an inactive (“dead”) form of Cas9, she would create a homing machine to seek out a target DNA sequence and unspool a short stretch of DNA (without cutting the strand) upon which the cytidine deaminase could act.
After about eight months, Komor had a prototype base editor working that could convert a C:G basepair into a U:G mismatch pairing. Now she faced a new problem: the cell’s DNA repair system won’t tolerate the mismatch, so it tries to restore a natural basepair, like finding the right match in a jigsaw puzzle. Facing this U:G intermediate, Komor needed to tip the odds to favor the solution she wanted—coax the cell to repair the G, which would result in an T:A basepair.I She had to find a trick to complete the base edit, rather than watch the cell’s DNA repair process simply undo her good work by fixing the U, reverting the base pairing back to where she’d started.